Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care—clinically relevant 3PM innovation

Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the “host” on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged “fellows” rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.

appropriate concentration.The overall process coordinates the life-important balance between anabolism and catabolism, namely, -On the one hand, biosynthetic pathways generating macromolecules by utilizing energy stored in a form of ATP (adenosine triphosphate) and NADPH (nicotinamide adenine dinucleotide phosphate) to generate macromolecules -On the other hand, catabolic pathways breaking down macromolecules into the pool of elements to cover the demand on building materials for anabolism and energy production Both parts of the whole depend directly on the healthy mitochondrial population as the powerhouse at cellular and organismal levels.
Despite their subordination in humans as a subcellular component of eucaryotic cells, to a great extent, mitochondria maintain their independent status over the entire history of symbiosis with humans, e.g., by keeping their genetic identity (mtDNA).Further, the high dynamicity of their homeostasis (fission versus fusion and mitophagy) allows mitochondrial population for promptly adapting under changing environment to remain within their comfort zone despite health risks at systemic level.Further, mitochondria and humans demonstrate life-important synergies: all compensatory mechanisms indicate that they learned to cooperate together on protecting life quality and minimizing health risks.Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body.As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery [1].Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals against disease progression) care [2].
The cause of compromized mitochondrial health ranges from preventable risks such as suboptimal lifestyle and dietary patterns (majority of affected individuals) to inherited or acquired mutations in chrDNA or mtDNA (mitochondrial diseases which create a minor portion).All systems in human body suffer from compromized mitochondrial health but the most affected are highly energy-consuming ones which are the heart, the central and peripheral nervous system, and skeletal and smooth muscles resulting in frequently fatal cardiac deficits (heart failure, sudden heart arrest), accelerated brain aging/neurodegeneration, and a spectrum of muscular pathologies.Further, also the kidney and pancreatic β-cells producing insulin belong to the tissues which are highly susceptible to defective mitochondrial oxidative phosphorylation [3].Impairments specifically in the mitochondrial oxidative phosphorylation can be caused by low energy and oxygen supply, e.g., under ischemic conditions and deficits of electron transport chain (ETC) enzymes and of electron carrier CoQ 10 .To this end, corresponding toxic effects are abundantly described, for example, for the alcohol abuse which inhibits mtDNA replication.Further, cocaine, cyanide, chloroform, acid, cholic acids, among others, are known to inhibit ETC enzymatic complexes I-IV.Above a certain threshold, the damage is irreversible, and the lack of ATP and uncoupled mitochondria are fatal for the affected cells then triggering apoptosis [3].However, below the threshold, targeted application of mitochondriarelated nutraceuticals may reverse the damage and stabilize corresponding conditions.For example, Ginkgo biloba stimulates ETC enzymatic complexes I and III, whereas melatonin stimulates ETC enzymatic complexes I and IV.Further, dietary CoQ 10 supplementation is recommended to treat cardiomyopathy-associated deficits as well as to compensate its plasma level concentrations usually reduced by therapeutical application of statins.
Mitochondrial diseases are highly heterogeneous from genetic and clinical points of view with no curation possible.Therapeutic strategies utilize a number of nutraceuticals to milden disease severity in corresponding medical conditions.To this end, CoQ 10 and vitamins B 1 and B 2 are recommended to support ETC efficacy, whereas creatine is used for energy buffering.Further, epicatechin is considered effective to stimulate mitochondrial biogenesis.Arginine and citrulline are used to restore nitric oxide production.Cysteine donors, vitamins C and E, and lipoic acid are utilized due to their antioxidant properties.Overall, individualized application of nutraceuticals is considered a promising approach to mitigate mitochondrial impairments [4].

Demand on individualized application of nutraceuticals in primary and secondary care
Nutraceuticals, a hybrid of nutrition and pharmaceuticals, also known as phytochemicals and functional foods, are naturally occurring bioactive chemical compounds demonstrating evidence-based health-promoting, illness-preventing, and other health-related benefits.Health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile have made them to the robust source of novel drugs and food industry products, as well as herbal and dietary supplements in traditional and innovative medical approaches [5].Keeping in mind these huge advantages, there is a permanently growing demand on individually adapted application of nutraceuticals in primary and secondary care.

Multi-faceted beneficial effects of flavonoids are linked to mitochondrial health and bioactivities affecting all functions at cellular and organismal levels
Flavonoids are naturally synthesized as bioactive secondary metabolites in various plant foods such as fruits, vegetables, nuts, whole grains, and medicinal herbs [6].More than 10,000 different flavonoid compounds have been isolated and characterized regarding their health-promoting effects; their beneficial effects are evidence-based and welldocumented [7].Depending on their chemical structure, flavonoids are divided into seven subfamilies: flavones, flavanones, flavonols, flavan-3-ols, isoflavones, anthocyanidins, and chalcones.The majority of these compounds possess strong antioxidant and radical scavenging, vasodilating/ antihypertensive, anti-inflammatory, immunomodulatory, antiangiogenic, anticancer, antiviral, antigenotoxic, antiallergenic, and antidepressant-like properties-all are of great clinical relevance [8,9].Their health beneficial effects are applicable early in life, e.g., in pregnant women diagnosed with preeclampsia [6]: targeted application of flavonoids suppresses pro-inflammatory pathways positively affecting vascular system by antihypertensive, antiatherogenic, antioxidant, antiplatelet, and vasodilating actions, thereby mitigating risks of maternal and fetal mortality and improving long-term individual outcomes [10].Directly or indirectly, beneficial health effects of flavonoids are linked to physiologic mitochondrial homeostasis and/or bioactivities affecting all functions at cellular and organismal levels [11][12][13].Since flavonoids have poor oral bioavailability, the gut microbiome plays a significant role in their absorption and metabolism.It is estimated that only 5-10% of dietary flavonoids are absorbed in the small intestine.The remaining 90% of consumed flavonoids are generally degraded via enzymatic processes by the large intestine's resident microbiota or excreted from the body; therefore, technological solutions which would allow for increased bioavailability of flavonoids are extensively under consideration by multiprofessional groups involved [10].

Mitochondrial sirtuins
Sirtuin is a protein family controlling senescence and longevity relevant processes by epigenetic regulation and balancing together the anabolism (biosynthesis process utilizing energy from ATP and NADPH to generate macromolecules) versus catabolism (the breakdown of macromolecules into smaller compounds further used to fuel anabolism).
Therefore, biological age to a large extent depends on the sirtuin functionality.The sirtuin family includes seven members SIRT1-SIRT7, of which SIRT3, SIRT4, and SIRT5 are predominantly localized at mitochondria and therefore referred to as mitochondrial sirtuins which bridge together metabolism, senescence, and longevity [14].
The silent information regulator 2 (Sir2) gene was identified in Saccharomyces cerevisiae for the first time.A study showed that it prolonged budding yeast's life span by inhibiting genome instability [15].SIR2-like genes, known as sirtuins, are abundant in most organisms, such as plants, bacteria, and animals, and contribute to their health and survival [16].The demonstration that sirtuins function as NAD + -dependent protein deacetylases (deacylases) opened up a novel avenue of research into the metabolic modulation of sirtuins and regulation of their activity by small molecules [15].As a result of deacetylation, cellular NAD + metabolism is integrated into a wide array of cellular mechanisms like cell metabolism, cell survival, cell cycle, cell death, DNA repair, mitochondrial oxidative metabolism and the consequent resistance to oxidative stress, and even life expectancy.The most widely investigated sirtuin, SIRT1, is located in the nucleus and cytosol and, along with histone deacetylation, controls transcription factors, such as p53, NF-κB, forkhead boxes (FOXOs), peroxisome proliferatoractivated receptor γ coactivator 1-α (PGC1α), and DNA repair proteins, such as PARP1.SIRT2 is a cytosolic sirtuin, while SIRT3, 4, and 5 are present in mitochondria and involved in oxidative stress and lipid metabolism.SIRT6 and 7 are in the nuclei and play a role in gene expression and DNA repair.Age-related reductions in NAD + levels and sirtuin activity are contributing factors in the pathogenesis of a wide variety of cardiovascular and metabolic disorders, including atherosclerosis, endothelial dysfunction, acute cardiac syndromes, cardiomyopathy, hypertrophy and heart failure, arrhythmias, hypertension, metabolic syndrome, obesity, fatty liver, diabetes mellitus, and dyslipidemia [17].A study in mice demonstrated that ageing is associated with an increase in CD38 activity, which is negatively correlated with NAD + levels and mitochondrial activity.In part, this response can be explained by a decline in SIRT3 activity.In light of the decline of sirtuin activity, the loss of NAD + levels is the primary cause of sirtuin inactivity, senescence, and ageing-related diseases [18].

PPAR-PGC-1 alpha axis
The PPAR-PGC-1α axis is a potential therapeutic target for the regulation of mitochondrial biogenesis and function in multiple serious diseases.
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein encoded by the PPARGC1A gene with a central role in the regulation of mitochondrial biogenesis and function.It is highly expressed in mitochondria-enriched tissues with high energy demands.Disorders in its expression, function, or PGC-1α-related pathways are significantly associated with the metabolic syndrome, pathogenesis of obesity, type 2 diabetes mellitus, cardiovascular and liver diseases, or cancer [19][20][21].The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor of the pleiotropic nuclear receptor 1C (NR1C) family (also known as the PPAR family) [22,23].In addition, they are known further isoforms of PPAR receptors, i.e., the peroxisome proliferator-activated receptors gamma (PPARγ) and beta/ delta (PPARβ/δ).Together, they are significantly involved in the metabolism of lipids and glucose in various tissues, and their dysregulation is associated with several diseases, including cardiovascular diseases, Alzheimer's disease, or diabetes mellitus.PPARα is particularly highly expressed in hepatocytes, cardiomyocytes, proximal renal tubular cells, and brown adipocytes, whereas PPARβ/δ in the cells of skeletal muscle, skin, adipose tissue, heart, or liver [23].
The PPARα-PGC-1α axis plays an important role in the regulation of cardiac function.In the myocardium, it controls fatty acid and glucose metabolism and mitochondrial biogenesis as well as mitochondrial energy metabolism [24,25].Research has shown that the expression levels of PPARα and PGC-1α were reduced in various experimental models of heart failure [25,26].The PPARβ can promote mitochondrial biogenesis by increasing expression of the nuclear respiratory factor 1 (NRF-1) and by stabilization of existing PGC-1α protein [27,28].It turned out that the PGC-1α/PPARβ axis has also an essential role in the induction of the uncoupling protein 3 (UCP3) expression, one of the important mitochondrial membrane proton transporters (UCPs) regulating lipid metabolism and mitochondrial production of reactive oxygen species [29].In the study of Lima et al. [29], the UCP3 protein expression affected fatty acid metabolism, PGC-1α-induced oxidative capacity, and the adaptive mitochondrial response to fatty acid exposure in skeletal muscle cells.In addition, the PPAR-PGC-1α axis is also a significant regulator of mitochondrial biogenesis in many other vital organs, including the brain, liver, kidney, or adipose tissue [25,28,30].

Senotherapeutics
Among mitochondria-targeting substances, senotherapeutic drugs have drawn a great deal of attention in a search of strategies to extend the healthspan and to prevent or treat age-related pathologies.Senotherapeutics include three classes: senolytics which selectively eliminate senescent cells; senomorphics, which modulate or reverse senescent cell phenotype; and mediators of the immune system clearance of senescent cells [41].
The first report on senolytics comes from 2015.Zhu et al. [42] found that quercetin (a natural product) and dasatinib (a synthetic product) eliminated senescent mouse embryonic fibroblasts and extended healthspan in mice.Since then, numerous reports on modulating senescence using senotherapeutics were published.Many of them belong to polyphenol group and have attracted attention mostly due to involvement in molecular pathways crucial for maintaining viability of tumor cells.Preclinical evidence shows that polyphenols exert greater selectivity in tumor cells to target oxidative phosphorylation and regulation of the mitochondrial membrane potential (MMP), glycolysis, pro-oxidant pathways, and antioxidant (adaptive) stress responses and their anticancer efficacy relates to the protonophoric and pro-oxidant properties rather than the specific effects on downstream molecular targets affected by MMP dissipation and mitochondrial uncoupling [43].

Quercetin
Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4Hchromen-4-one), a flavonoid from a flavonol group, and its derivatives possess antioxidant properties and strongly influence cellular lifespan, survival, and viability.A series of preclinical studies demonstrated antiageing and rejuvenating effects of quercetin [44].Specifically in senescent fibroblasts, improved homeostasis and significant rejuvenation have been reached by quercetin supplementation.The mechanisms of the observed rejuvenation rely on the Sirt1agonist function of quercetin and restoring physiologic levels of mitophagy and renewing functional populations of mitochondria [1].Strong health beneficial effects of quercetin supplementation are demonstrated in the reproductive medicine-related research such as overall quality, viability, and motility of sperm linked to improved parameters of the mitochondrial health [45].
Involvement of quercetin in mitochondrial processes is well-documented [58].Preclinical research showed that quercetin supports mitophagy and modulates mitochondrial biogenesis, MMP, oxidative respiration, and ATP anabolism as well as intramitochondrial redox status [50].Quercetin has also drawn attention due to purported improvement of endurance exercise capacity.Quercetin upregulates SIRT1 and PGC-1α, increases mtDNA and cytochrome c content in the muscle and brain, increases endurance performance in rodents [59], and prevents muscle atrophy in denervated mice [60], although, for example, an exercise performance is not influenced by quercetin supplementation in humans [61].Quercetin combined with dasatinib synergistically decreases senescent cell burden in patients with diabetic kidney disease [62].
In summary, data collected regarding health benefits of quercetin are encouraging.Currently, a clinical study evaluating the effect of quercetin and another senolytic substance fisetin on skeletal health in older subjects is ongoing [63].It must be considered, though, that in general population, the direct absorption of the quercetin glycosides from plant sources is negligible and the hydrolysis to more lipophilic aglycones is necessary for absorption.Further, the bioavailability of senolytics depends on the type of glycoside [50], individual genetic polymorphisms, composition of gut microbiota, and drug exposure, among others [64].Improved quercetin formulations for oral administration, e.g., based on lecithin with better solubility and absorption, have been proposed [65].
It seems that modulation of cell signaling pathways by fisetin differs in cancer cells compared to normal cells [72].Fisetin protects cells from apoptosis by targeting both intrinsic and extrinsic apoptotic pathways and enhances proliferation through upregulation of cell cycle activators [69].In cancer cells, however, fisetin exerts antiproliferative and pro-apoptotic effects via activation of both death receptor and mitochondrial-dependent pathways [73,74] and inhibits cell migration, metastatic activity, and angiogenesis [75][76][77].The anticancer properties of fisetin can be attributed to regulation of several signaling pathways, including MAPK, NF-κB, PI3K/Akt/mTOR, vascular endothelial growth factor, and Nrf2/HO-1 (transcription factor nuclear factor erythroid 2-related factor 2/heme oxygenase 1) [78].
Fisetin treatment upregulates PGC-1α and TFAM (mitochondrial transcription factor A) mRNA levels, increased mtDNA copy number, and mitochondrial mass in neuronal cells.Fisetin also modulates expressions of anti-Parkinson's molecular panels involved in neuroprotection and neuronal differentiation [79].In vivo fisetin increases mitochondrial ATP production in ischemia-reperfusion insult hearts by activating electron transport chain complex 1, thus preserving the function of interfibrillar mitochondria [80].Fisetin improves mitochondrial dysfunction and impairment in palmitate-treated hepatocytes and attenuated non-alcoholic fatty liver disease in mice fed a high-fat diet [81].A rigorous study from 2018 [82] showed that out of the 10 flavonoids tested (including resveratrol, quercetin, ECGC, and curcumin), fisetin had the most potent senolytic effects against several cell types in vitro.Fisetin reduced markers of senescence and senescence-associated secretory phenotype in multiple tissues, extended the healthspan, and prolonged the lifespan in mice [82].
Preclinical research revealed the beneficial effects of this flavonol in neurodegenerative, cardiovascular, metabolic, and cancer diseases, but these results have to be verified in human subjects.A clinical trial showed that fisetin may improve the treatment of brain ischemic stroke [83].Other clinical trials evaluating the effects of fisetin on vascular function in older adults and alleviation of frailty in older subjects or in cancer survivors are currently underway [84][85][86][87].It has to be considered, though, that the bioavailability of fisetin after oral administration is poor, so it is necessary to develop an effective delivery method to enhance its therapeutic potential in treatment of a particular disease, e.g., using nanotechnologies [88].
Piperlongumine has drawn attention mostly to its anticancer activity attributed to modulation of various pathways, e.g., PI3K/PKB/mTOR, NF-κB, JNK/STAT3 (Janus kinases/ signal transducer and activator of transcription 3).Piperlongumine affected various hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelialmesenchymal-transition, and metastases and also inhibited radioresistance and chemoresistance of cancer cells [90][91][92].Piperlongumine targeted various types of cancer cells selectively, with minimal toxicity to normal cells [93,94].Piperlongumine showed cytotoxic effects in human cancer cells via increased intracellular ROS production and subsequent mitochondrial dysfunction [90,[95][96][97].Piperlongumine reduced the migration and colony formation in breast cancer cells through multiple mechanisms including modulation of glucose import, NF-κB activation, and lncRNA expression.In the same study, piperlongumine also enhanced the efficacy of doxorubicin on mammary tumor growth in vivo [92].Piperlongumine inhibited experimental colon cancer via Ras/PI3K/Akt/mTOR signaling axis and induced mitochondrial apoptotic pathway by downregulating Bcl-2 levels [93].Inhibition of cell growth and induction of apoptosis by piperlongumine were also reported in human melanoma cells, via ROS-mediated mitochondria disruption and JNK (p-Jun N-terminal kinase) pathway [90].Apart from anticancer effects, antinociceptive, anxiolytic, antidepressant, antiatherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities were reported too [98].
Human data on piperlongumine are missing, apart from a single clinical study in Japanese women which showed that Piper longum extract increased peripheral blood flow and skin temperature after cold stress [99].Piperlongumine seems to be very safe in vivo [98]; however, the limited bioavailability and hydrophobicity restrict its application.More efficient delivery methods, e.g., using nanoformulation, may result in better therapeutic effect [100].A drug interaction has to be considered with piperlongumine administration as it was reported to inhibit CYP1A2 isoenzymes [101].

Curcumin
Curcumin, a (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, is present in the rhizome of Curcuma longa.It is one of the primary components in turmeric and curry ingredients that are often used as flavoring agents in Asian and Middle Eastern countries [102].Mango ginger, also known as Curcuma amada, belongs to the ginger family Zingiberaceae.It contains curcuminoids and curcumin but in much smaller amounts compared to turmeric [103].
Curcumin shows significant beneficial effects on human health, which include anti-inflammatory and antioxidative effects.Moreover, curcumin has substantial neuroprotective activities against a broad spectrum of xenobiotics [104].In addition, curcumin has been proven to control hyperlipidemia, metabolic syndrome, arthritis, and anxiety [105].Cumulative research data pointed to curcumin as a molecule which elevates mitochondrial functions in various preclinical and clinical conditions [106,107].
The neuroprotective effects of curcumin via effects on mitochondrial functions are well-documented.Curcumin demonstrated protective activities against oxygen-glucose deprivation/reoxygenation-induced injury in astrocyte primary cells in vitro through the elevated mitochondrial function and triggering the ERK signaling pathway [108].In another study, curcumin demonstrated neuroprotective activities against amyloid-β-induced mitochondrial dysfunction which were associated with the inhibition of the GSK-3β signaling pathway [109].Miao et al. [110] described that curcumin administration suppressed inflammation and mitochondrial dysfunction in experimental stroke through the activation of Sirt1 cell signaling.Anti-inflammatory activity and positive effects on the mitochondrial function of curcumin were documented in the study using a liver steatosis model in obese mice [111].Curcumin affected several mechanisms of action such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) gene signaling and reduced hepatic NF-κB signaling.Besides that, curcumin normalized mtDNA and restored mitochondrial oxidative metabolism and biogenesis [111].Regarding the metabolic activities of curcumin, it improved mitochondrial dysfunction which correlated with the suppression of gluconeogenesis in free fatty acid-regulated hepatic lipoapoptosis [112].Curcumin also upregulated cell signals regulating mitochondrial biogenesis, i.e., including peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), NRF1, and TFAM.In the model of osteoarthritis, curcumin was documented as an activator of mitophagy in preserving mitochondrial function (ROS, Ca 2+ , ATP synthesis, and mitochondrial membrane potential).In this study, curcumin showed significant chondroprotective effects in the model of osteoarthrosis via the activation of the AMPK/ PINK1/Parkin cell signaling [113].
Most, if not all, cell types in the organism, including the cardiovascular and nervous system, depend on appropriate mitochondrial function.It has been described that curcumin has outstanding neuro-and mitochondria-protective effects against wide-spectrum neurotoxic substances involved in the multi-step process of neurodegenerative diseases' development [104].Curcumin has considerable clinical potential in other chronic diseases such as cardiovascular and metabolic diseases or cancer [114][115][116].For the introduction of curcumin into clinical practice, more standardized clinical trials are required to fully uncover its preventive and therapeutic potential in clinical practice.
Mitochondrial impairment-related disorders are ameliorated by resveratrol mainly through the redox-dependent mechanisms.Resveratrol upregulates mitochondrial antioxidative enzymes and triggers mitochondrial biosynthesis, thus acting as mitochondrial protective substance [133,134].Unfortunately, human data focusing on the impact of the resveratrol on mitochondrial function are scarce, with limited number of subjects involved.Resveratrol supplementation in obese patients mimicked the effects of caloric restrictionactivation of AMPK, increase in SIRT1 and PGC-1α protein levels, increase in citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration were found [135].However, positive effect of resveratrol on muscle mitochondrial function was not confirmed by other reports [136,137].Resveratrol ameliorated mitochondrial respiratory dysfunction in patient-derived fibroblasts carrying homoplasmic mtDNA mutations [138].Resveratrol triggered apoptosis via the involvement of mitochondrial pathway in fibroblast-like synoviocytes derived from patients with rheumatoid arthritis [139] and was proved as an effective adjuvants in the management of rheumatoid arthritis patients [140].Improvement of skeletal muscle mitochondrial functions was seen in older patients when resveratrol was combined with exercise [141].An ongoing clinical study investigates the effect of 12-week resveratrol administration on skeletal muscle mitochondrial function in people with type 1 diabetes [142].
Safety concerns regarding resveratrol supplementation emerged as some preclinical reports showed that, depending on the concentration and the cell type, resveratrol may also amplify oxidative stress [143] and induce mitochondrial dysfunction associated with bioenergetic impairments and/ or apoptosis triggering [144].So, despite large evidence of beneficial effects of resveratrol in diseases associated with mitochondrial dysfunction (e.g., Alzheimer's disease, Parkinson's disease, muscle atrophy, cardiovascular disease, arthritis, obesity, and cancer) [129], adverse effects in normal cells have to be considered [145].In addition, doses proved to be efficient in preclinical research, e.g., against cancer cells by in vitro assays, largely exceed those which may be achieved by dietary intake, and, moreover, resveratrol possesses a low bioavailability as it is rapidly metabolized [146].Resveratrol-drug interaction using high dosage due to inactivation of CYP450 isoenzymes is also of concern [147].Therefore, the dose and formulation of resveratrol for human use should be carefully considered.
Kaempferol improved mitochondrial function in lungischemia reperfusion injury both in vitro and in vivo.Kaempferol increased the cell viability, improved MMP, inhibited the opening of mitochondrial permeability transition pores, reduced the levels of oxidative stress and apoptosis, increased the expressions of Bcl-2 and mitochondrial cytochrome c, and decreased the expressions of Bax and cytoplasmic cytochrome via SIRT 1/PGC-1α signaling pathway [165].Upregulation of the mitochondrial quality control proteins PGC-1α and also PINK1, Parkin, and Beclin was reported in another study [151].
Preclinical evidence regarding beneficial health effects of kaempferol is promising but human data are scarce.Epidemiological studies showed that high intake of kaempferol is associated with non-significant decrease in incidence of several types of cancer; however, potential confounding factors could bias estimates of risk [166].Clinical studies are needed to elucidate the association between kaempferol intake and incidence of cancer and other pathologies, but first, it is necessary to evaluate the safety of its excessive use.A recent randomized, placebo-controlled trial showed that the consumption of 50 mg kaempferol aglycone daily for 4 weeks is safe in healthy adults [167].The bioactivity of kaempferol, which depends on the ingested conjugate, must be considered; however, human reports on the bioavailability of dietary kaempferol are missing [168].
Vast evidence exists on apigenin alleviation of various pathologies by targeting mitochondria.He et al. [182] reported that apigenin induced mitochondria-dependent apoptosis in hypoxic pulmonary artery smooth muscle cells and protected against pulmonary hypertension via inhibition of the hypoxia-inducible factor 1α-KV1.5 channel pathway.Apigenin has a potential to alleviate non-alcoholic fatty liver disease; a decrease of hepatic lipid accumulation by activating the autophagy-mitochondrial pathway in human hepatoma cells was reported [183].In an animal model of acute myocardial infarction, apigenin attenuated cardiomyocyte injury by modulating Parkin-mediated mitochondrial autophagy [184].Apigenin attenuated copper-mediated β-amyloid neurotoxicity in an Alzheimer's disease cell model, through regulation of redox imbalance, preservation of mitochondrial function, MAPK pathway inhibition, and inhibition of neuronal apoptosis [185].Apigenin may also be beneficial in immune disorders and chronic asthma.To this end, a non-eosinophilic inflammation, dysregulated immune homeostasis, and mitochondria-mediated airway epithelial cell apoptosis were ameliorated via the ROS/ASK1 (apoptosis signal-regulating kinase 1)/MAPK pathway after apigenin treatment [186].Clinical studies evaluating apigenin are being prepared/ongoing, regarding its effect in rheumatoid arthritis, Parkinson's disease, and improvement of organ function in elderly patients with sepsis [187][188][189].However, it is not likely that effective plasma concentrations may be achieved by dietary ingestion of apigenin-containing plant materials; therefore, strategies to improve the delivery and access of apigenin by the target tissues are needed, such as use of liposomes or nanostructured lipid carriers [190,191].
Vitamin D through the specific receptor (vitamin D receptor, VDR) affects the function of the central nervous system (neurons, microglia, and astrocytes), the cardiovascular system (vascular smooth muscle cells, pericytes, endothelial cells, and cardiomyocytes), tissue healing (fibroblasts), and epithelium [195].
Within the central nervous system (CNS), vitamin D signaling plays a fundamental role in brain development, neuroprotection, neurotransmission, and immunomodulation.In addition, vitamin D represents an essential protective mechanism in the CNS, which enhances mitochondrial brain energy metabolism [196].Vitamin D-linked molecular pathways in the CNS are triggered through the VDR, a zinc-finger protein structure within the nuclear receptor superfamily.However, the precise signaling pathways by which vitamin D realizes mentioned activities in the CNS are poorly understood [197].In the cardiovascular system, 1,25(OH) 2 D 3 vitamin form inhibits renin gene expression by affecting the cyclic AMP signaling, a pathway that shows a crucial activity in renin biosynthesis/release as a response to different physiological stimuli [198].In this regard, vitamin D-mitochondrial function cross-talk could affect the cellular signaling involved in the development of hypertension [199].Recent data showed that the beneficial effects of vitamin D in mitochondria-mediated cardiovascular effects are observed mainly in cardiomyocytes [200].In addition, 1,25(OH) 2 D 3 reduces fibroblast differentiation and ECM formation via Smad2/3-dependent TGF-β1 signaling pathways [201] and the activation of VDR signals suppressed TGFβ-mediated EMT in a model of renal fibrosis [202].Fiz et al. [203] found that TGFβ/vitamin D interplay positively modulates mitochondrial activity in human pancreatic cancer cells.It was documented that activated VDR inhibits EMT through the modified epithelial mitochondrial function during the process of fibrosis [204].
In addition to above-mentioned mitochondria-relevant functions of vitamin D, activated VDR rewires cell metabolism towards the biosynthetic pathways.Decreased vitamin D levels reduce mitochondrial activity and ATP production from oxidative phosphorylation and increase oxidative stress and inflammation [205,206].Vitamin D-controlled mitochondrial health may also have implications for self-renewal capacity of cells [207].
Vitamin D is an important substance for skeletal muscle and bone support in humans.The regeneration of muscle includes complex mechanisms comprising the restoration of mitochondrial functions [207].More specifically, vitamin D 3 therapy increased mitochondrial oxidative phosphorylation in muscle cells after exercise in symptomatic, vitamin D-deficient subjects [208].Another study revealed that vitamin D deficiency is linked with muscle atrophy, increased oxidative stress, and decreased mitochondrial functions in the multifidus muscle in patients [209].Regarding bone health, hypovitaminosis D represents a risk factor for decreased bone strength in primary mitochondrial disease in human subjects [210].

Silibinin
Silibinin (or silybin), a (2R,3R)-3,5,7-trihydroxy- [1,4]dioxin-6-yl] chroman-4-one, is a flavonolignan, a natural polyphenolic flavonoid.Silibinin is a major bioactive component of Silybum marianum L. fruit extract called silymarin.Silibinin itself is a mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio.Silibinin is not only the major silymarin compound but is also the most bioactive substance of this extract which is widely used as a traditional medicine for liver diseases in Asia and Europe [211,212].
Silibinin has been described as a substance with significant pharmacological activities, i.e., hepatoprotective, cardioprotective, neuroprotective, hypocholesterolemic, antioxidant, anticancer, or antiviral [213][214][215][216][217][218][219].In this regard, silibinin has been found to be a potentially effective substance in the modulation of mitochondrial dysfunction and the consequence formation of reactive oxygen/nitrogen species that are included in the initiation and progression of chronic liver disease, age-related neurodegenerative disorders, and other chronic diseases [220,221].
More specifically, it has been described that the modulation of AMPK signaling of mitochondrial function may be a key in the development of human steatohepatitis.Salomone et al. reported that silibinin renews cellular NAD + levels and activates the SIRT1/AMPKp pathway in non-alcoholic fatty liver [222].In another study, silibinin suppressed ischemia-reperfusion injury-induced mitochondrial dysfunction and ER stress.This silibinin-induced cardioprotection was linked with downregulated apoptosis, inflammation, and oxidative stress via the inhibition of NF-κB signaling [223].In addition, neuroprotective activities of silibinin were found after cerebral hypoxia/reoxygenation injury through the activation of the GAS6/Axl cell signaling [215].The JNK/SAPK-activated signaling after silibinin treatment was responsible for mitochondrial apoptosis in pancreatic carcinoma [224].Finally, silibinin suppressed the presence of endometriotic lesions through the downregulation of proinflammatory cytokines in mice via the anti-inflammatory modulation of MAPK signaling [225].
The above-mentioned findings point to silibinin as a clinically promising substance that can be further developed as a therapeutic candidate for the prevention and treatment of chronic diseases in humans.The characteristic of silibinin to alleviate mitochondrial failure is part of its beneficial properties; however, future clinical research with larger patient samples and longer duration is needed to elucidate its clinical contribution in this regard [226].
In clinical sphere, allicin has been assessed in several human diagnoses, such as the management of cold, hypertension, rheumatoid arthritis, hypercholesterolemia, diabetes, and nephrotoxicity, or its protective role was evaluated in atherosclerosis and cancer disease.Numerous research data described possible cardioprotective effects by causing vasorelaxation and the moderation of certain pathological conditions of cardiovascular diseases, including cardiac hypertrophy, platelet aggregation, angiogenesis, and metabolic disorders such as hyperlipidemia or hyperglycemia [228,229].
Allicin was documented as a mitochondrial dysfunction-alleviating substance in different cell types [230][231][232].In this regard, allicin with its antibacterial activities ameliorated sepsis-triggered acute kidney injury via activation of Nrf2/HO-1 cell signaling [233].Using an in vitro model of primary porcine cardiomyocytes, allicin decreased mitochondrial injury, myocardial apoptosis, and inflammation during hypoxia-reoxygenation via modulation of several signaling pathways including PPARγ coactivator 1α, endothelial NO synthase, endothelin-1, HIF-1α, and TGF [232].In the model of intervertebral disc degeneration, allicin protected the nucleus pulposus cells against advanced oxidation protein product-modulated mitochondrial dysfunction and oxidative stress through the downregulation of the p38-MAPK signaling pathway [234].Regarding nephroprotective effects, allicin improved mitochondrial dysfunction in acrylamide-induced nephrotoxicity in rats through the upregulation of the SIRT1 signaling pathway [235].In another study evaluating the cardioprotective effects of allicin, the suppression of lipopolysaccharide-induced oxidative stress and inflammation was observed in human umbilical vein endothelial cells.The authors summarized that these effects were caused by the alleviation of mitochondrial dysfunction and increased activity of Nrf2 signaling [236].Besides that, allicin shows sensitizing activity on hepatocellular cancer cells to 5-fluorouracil therapy via the activation of ROS-mediated mitochondrial pathway associated with the modulation of caspase-3/PARP/Bcl-2 signaling [237].Finally, allicin was responsible for the neuroprotection of PC12 cells against 6-OHDA-triggered mitochondrial dysfunction and oxidative stress through the modulation of mitochondrial dynamics (Opa-1/Fis-1/Drp-1 signaling) [230].
As we mentioned above, allicin shows significant antimicrobial, cardioprotective, neuroprotective, anti-inflammatory, metabolic, or anticancer effects.Based on these data, allicin possesses a clinical potential in developing effective therapeutics.However, due to the absence of valid clinical data so far, it is necessary to define the safe and effective doses of allicin for its application against specific diseases within in-depth evaluations.Only clinical trials and quality control studies can solve the beneficial introduction of allicin into clinical practice [238].

Ginsenosides
Research has further established that mitochondria are one of the most important targets of ginsenosides.
Ginsenosides are the main active ingredients of medicinal herbs from Panax species, such as Panax ginseng (Asian, Chinese, or Korean ginseng) and Panax quinquefolius (American or North American ginseng).They are found in all the tissues of ginseng, including roots, leaves, stems, or fruit [239].Based on a chemical structure, ginsenosides can be subdivided into three groups, i.e., protopanaxadiols (PPD-type), protopanaxatriols (PPT-type), and oleanolic acid (OA).With exception of OA, ginsenosides are tetracyclic dammarane-type saponins [240].The major ginsenosides found in both ginsengs are the Rb1, Rb2, Rb3, Rc, Rd, and Rg3 from PPD type; further, the Rf, Re, Rg1, and Rg2 from PPT-type; and several others [241,242].
Ginsenosides showed cardio-and neuroprotective effects by regulating mitochondrial energy metabolism, biosynthesis, apoptosis, mitophagy, or the status of membrane channels [245,[263][264][265].Many experimental studies also demonstrated that ginsenosides possess significant antioxidant effects and played the important role in maintaining the structural and functional integrity of mitochondria.They were involved in regulating multiple oxidative stress-related signaling pathways, such as the Keap1/Nrf2/ARE, PI3K/ Akt, Wnt/β-catenin, and NF-κB signaling pathways [248].In addition, ginsenoside Rg1 exerted antiapoptotic effect on non-alcoholic fatty liver cells.It downregulated the expression of SGPL1 and Bax proteins and upregulated the expression of Bcl-2, indicating that ginsenosides could promote the stability and integrity of the mitochondrial membrane [266].
Although ginseng is used in clinical settings worldwide, most studies on the pharmacological effects of ginseng and its ginsenosides are at the experimental level.Related evaluation of their clinical application is still rare [267].Jung et al. [268] have proven a favorable effect of ginseng on mitochondrial function and anabolic hormones in men with metabolic syndrome in their clinical study.The antioxidant effects of ginseng were demonstrated in clinical study of Yang et al. [269] when ginseng significantly decreased the level of serum ROS and methane dicarboxylic aldehyde activity in healthy volunteers.Kwon et al. [270] reported a beneficial effect of ginsenosides on cholesterol homeostasis in postmenopausal women with hypercholesterolemia, suggesting possible chemoprotective effects of ginsenosides against more severe cardiovascular diseases in this group of women.The meta-analysis of randomized clinical trials has showed that ginsenoside Rg3 can enhance drug efficacy and reduce drug-induced toxicity from chemotherapy in advanced non-small cell lung cancer patients [271].However, further research is also needed to elucidate the underlying mechanism of action, pharmacokinetics, and pharmacodynamics of ginsenosides, to expand theoretical and experimental basis for their clinical interventions.
In addition to above-mentioned activities, OA and its derivatives possess important mitochondria-relevant functions.They are for example important inducers of mitochondrial-dependent apoptotic pathway.They can alter mitochondrial membrane potential, release caspase activators into the cytoplasm, alter expression levels of pro-as well as antiapoptotic enzymes, and lead to overexpression of ROS and fragmentation of DNA molecule and ultimately to the tumor cells apoptosis [278,280,288,[308][309][310].Gong et al. [311] also showed the protective effect of OA in in vivo model of cardiac ageing via regulation of mitochondrial integrity.
The most studied OADs in clinical trials is CDDO-Me.Based on experimental studies, it is the important Nrf2 pathway activator and NF-κB pathway inhibitor.In clinical trials, CDDO-Me demonstrated antitumor activity in phase 1 for advanced solid tumors and lymphoma [279].Its therapeutic effect was also proven in phase 2 and 3 clinical trials for chronic kidney disease through a significant increase of eGFR and reduction of the loss of kidney function [312][313][314].In addition, CDDO-Me increased endothelial NO bioavailability and reduces vascular remodeling in a phase 2 trial for connective tissue disease-associated pulmonary arterial hypertension [315].CDDO-Me has also exhibited positive therapeutic effects in clinical trials for diabetic nephropathy [316].

Melatonin
Melatonin (N-acetyl-5-methoxytryptamine, N-[2-(5-methoxy-1H-indol-3-yl) ethyl] acetamide) is mostly known as a pineal gland hormone, but in vertebrates, pineal melatonin represents only 5% or less of the total amount generated [317].Melatonin is an ubiquitous molecule synthesized not only by animal taxa but also by unicellular, bacteria, fungi, and plants [318,319].Melatonin content in plants varies greatly (concentrations ranging from 1 ng to 6 μg/g), dietary sources rich in melatonin include coffee beans, goji berries, white radish, apples, cherries, and tomatoes, but even higher levels were found in medicinal and aromatic plants, particularly thyme (38 μg/g), Chinese liquorice, sage, and St. John's wort [320].However, phytomelatonin levels depend on ripeness stage and postharvest conservation and, in addition, abiotic stressors modulate its production; therefore, the level may differ within the same plant species depending on environmental conditions [320,321].Melatonin intake from animal-source foods is usually lower than from plant food (concentrations ranging in ng/g) [322].
Melatonin regulates numerous physiological processes including circadian rhythms, sleep, metabolism, reproduction, cardiovascular, immune, and hematopoietic systems [323][324][325].Melatonin is a well-known ROS/RNS scavenger but exerts its antioxidant activities also through indirect mechanisms, e.g., by enhancing the activity of mitochondrial electron transport chain, activation of antioxidative, and inhibition of pro-oxidative enzymes and enhancing the DNA repair [326,327].Alleviation of oxidative stress is only one of the many properties of this indoleamine with potential to prevent/reverse various pathological conditions; others include modulation of the cell cycle, apoptosis, modulation of oncogene expression, immunomodulation, and inhibition of angiogenesis [324,328].
Mitochondria-related beneficial effects of melatonin are well-known [329,330].Melatonin protects mitochondria by eliminating ROS, inhibiting the mitochondrial permeability transition pore, and activating uncoupling proteins, thus maintaining the optimal MMP and preserving mitochondrial functions [331].Melatonin also modulates mitochondrial dynamics which include improvement of mitochondrial biogenesis [332], mitochondrial fission/fusion [333], and autophagy/mitophagy [334].Melatonin promoted AMPK phosphorylation and accelerated the translocation of PINK1 (PTEN-induced kinase 1) and Parkin to the mitochondria, thereby activating mitophagy [335].Another study showed that melatonin promotes mitophagy through upregulation of SIRT1 and downregulation of forkhead transcription factors class O (type1) (FoxO1) [336].Mitophagy maintains functional mitochondria by degradation of disrupted or redundant mitochondria, but, on the other hand, dysregulated mitophagy may result in mitochondrial dysfunction and thus promote chronic disorders, including ischemia/ reperfusion-related diseases in vital organs, neurodegenerative conditions, and cancer [337].Induction or inhibition of autophagy/mitophagy by melatonin is based on cellular needs and oxidative stress levels [338][339][340][341].
Human data indicate that melatonin acts as a cardioprotective [342] and neuroprotective molecule in disorders where oxidative damage has been implicated as a common link [343].However, data regarding the actual impact of melatonin on mitochondrial function from clinical studies are scarce.In patients with Parkinson's disease, high melatonin dose (25 mg) recovered platelet mitochondrial function and diminished serum markers of oxidative stress [344].Supplementation with melatonin promoted the development of immature human oocytes retrieved from the controlled ovarian hyperstimulation by protecting mitochondrial function; upregulation of genes associated with ATP generation, increase in the MMP, and decrease in the intracellular ROS and Ca 2+ levels was found [345].Assessment of the anticancer efficacy of melatonin in clinical studies was inconsistent due to varied dosages and times of administration [346].Nevertheless, as cancer and other pathologies such as diabetes, gastrointestinal, neurodegenerative, and other diseases are related to mitochondrial dysfunction, regulation of mitochondrial homeostasis by melatonin may play a significant role in these pathologies [347].
In general population, melatonin is used for jet lag alleviation and sleep induction; over-the-counter supplements usually contain 1-5 mg.Melatonin short-term use is considered safe, even in higher doses; only mild adverse effects, such as dizziness, headache, nausea, and sleepiness have been reported.Safety of long-term use and use in children and adolescents, pregnant and breast-feeding women, and people with specific medication, however, requires further investigation [348][349][350][351].

Coenzyme Q 10
Coenzyme Q 10 (CoQ 10 ) originally isolated from beef heart is a vitamin-like molecule also synthesized by human cells acts an essential element of the mitochondrial respiratory chain, mobile electron carrier, membrane stabilizer, and redox-regulated modulator of molecular signaling and gene expression mechanisms [352,353].Cell membranes and mitochondria both contain reduced (ubiquinol) and oxidized (ubiquinone) forms of CoQ 10 .Fish, chicken legs, herring, and trout are usual foods sources of CoQ 10 : 3-5 mg is estimated to be physiologically consumed daily [354,355].In tissues with particularly high energy demands such as the heart, skeletal muscles, and neurons, CoQ 10 is abundantly concentrated indicating its prioritized bioenergetic function [352,356].Further, CoQ 10 's antioxidant activity is attributed to its reduced form capable to mitigate oxidative damage to sub/cellular structures and lipid peroxidation and to regenerate other antioxidants such as vitamins C and E in the body.CoQ 10 exhibits anti-inflammatory action by modulating NF-κB-dependent molecular pathway [355].
CoQ 10 deficiencies may occur due to genetic and mitochondrial diseases, imbalanced oxidative stress and suboptimal dietary habits, accelerated ageing, carcinogenesis, and health adverse effects of statin treatments, among others.
Low levels of CoQ 10 are characteristic for mitochondriopathies, diabetes mellitus, cancers, cardiovascular and cerebrovascular diseases including but not restricted to the heart failure, myocardial infarction, migraine, chronic kidney disease, and hypertension, neurodegenerative disorders including Alzheimer's and Parkinson's disease, and muscular dystrophy.In contrast, CoQ 10 treatment improves muscle endurance, decreased fatigue during daily duties, and reduced serum lactate and pyruvate levels.Treatment with oral CoQ 10 is often used to support mitochondrial health, sufficient energy, and antioxidant activity to prevent and mitigate many medical conditions [355,357].

L-Carnitine
Carnitine (3-hydroxy-4-N-trimethylammoniobutanoate) profiling is a useful diagnostic and prognostic tool for a wide range of diseases involving carnitine deficiency and poor fatty acid oxidation such as patients diagnosed with metallic disorders, e.g., diabetes mellitus predisposed to cascading complications, neurotoxicity, and mental disorders [1].Carnitine is synthesized in the human body using amino acids: L-lysine and L-methionine [358].Vitamin C, vitamin B 6 , niacin, and reduced iron act as cofactors in the synthesis of carnitine [359].Since only 25% of carnitine is synthesized endogenously, humans obtain carnitine substantially from their diet, primarily from meat, poultry, fish, and dairy products [360].The biologically active stereoisomer, L-carnitine, transports long-chain fatty acids from the cytoplasm to mitochondria for the energy production via beta-oxidation pathway via acetyl-CoA formation, removing short-and medium-chain fatty acids protecting mitochondria against their accumulation.LC controls pyruvate dehydrogenase activity by interacting with acetyl-CoA and maintaining acetyl-CoA/CoA ratios in the cell [359,361].LC also regulates the metabolic processes engaged in skeletal muscle protein balance: proteolysis and protein synthesis.Contextually, LC may be able to mitigate muscle damage that results from exercise because of its antioxidant and antiinflammatory properties [361].Acetylated LC form, acetyl-L-carnitine (ALC), is a well-tolerated nutraceutical substance.As a well-acknowledged "mitochondrial nutrient," ALC mitigates mitochondrial stress, therefore, protecting mitochondrial populations against burnout.Consequently, ALC demonstrates beneficial effects as a potent protector against stress-related disorders and ageing.Hence, ALC dietary supplementation is considered a promising approach for targeted treatments of severe medical conditions including heart failure, angina pectoris, obesity with complications, cancers, and diabetes mellitus with comorbidities [362].Last but not least, physiologic ALC concentrations are essential for high CNS performance considering their brain antiageing effects and direct involvement of antidepressant mechanisms including serotonergic, noradrenergic, and GABA neurotransmission pathways [1].

Creatine
Creatine plays a central role in all high energy demanding systems such as the CNS and muscular system under intensive sport training; these effects of creatine are per evidence associated with its bioenergetic role in the mitochondria [363].The entire spectrum of the systemic creatine involvement includes direct and indirect activities as an antioxidant and immuno-and neuromodulatory agent.Basically, human cells store only a small amount of ATP.Through the degradation of phosphocreatine, energy is released which is utilized for resynthesizing ADP and Pi back to ATP to preserve cellular function until glycolysis in the cytosol and oxidative phosphorylation in the mitochondria can generate adequate amounts of ATP for metabolic requirements.As an essential component of cell bioenergetics, creatine also facilitates the movement of Pi from mitochondria into the cytosol to form phosphocreatine (i.e., the creatine phosphate shuttle).As a result, phosphocreatine donates its phosphate to ADP to restore ATP for cellular functions, allowing creatine in the cytosol to diffuse back into the mitochondria for transport of the next phosphate farther from its production site.An increase in muscle phosphocreatine and creatine serves as an energy source to meet anaerobic energy demands, thereby providing a vital energy source especially during ischemia, injury, or impairment of mitochondrial function [364,365].
Creatine is one of the most extensively used dietary supplements globally, with a market value estimated to reach $520 million by 2024 [366].After being discovered in 1832 by French chemist Michel Eugène Chevreul as a constituent of skeletal muscle, creatine was studied as a food additive in the early 1990s.Creatine supplementation remains unquestionably crucial for boosting exercise performance.In recent years, novel studies have provided evidence of its healthpromoting properties outside of the athletic field, for example, in the treatment of neuromuscular and cardiometabolic diseases, posttraumatic rehabilitation, and ageing [367].The most common source of creatine is animal-based foods, such as human breast milk, infant formulas, meat, poultry, and fish, as well as dietary supplements that contain synthetically prepared and purified creatine, primarily in the form of creatine monohydrate.In contrast, all plant-based foods do not contain creatine [368].Result of the recent study in the US population reported possible creatine shortage from food with the average intake almost 50% lower than anticipated.At the same time, about 60% of young individuals consumed creatine below a threshold level of 1 g per day, and 17% consumed zero creatine.Lower meat consumption among the general population may contribute to inadequate creatine consumption [369].
Under various physiological (e.g., exercise, pregnancy, and lactation) and pathological circumstances (e.g., tissue trauma, ischemia, and diabetes), endogenous creatine synthesis is inadequate for humans [370].Taking creatine supplements first boosts skeletal muscle strength, power, and mass, particularly in athletes and bodybuilders who consume little meat [370].Another benefit of creatine supplementation in elderly subjects is the amelioration of sarcopenia, a condition marked by loss of muscle mass and function [371].Further, creatine supplementation improves the health of patients with neurological and muscular disorders [372].So a sufficient intake of dietary creatine may be vital for the maintenance of homeostasis and optimal health in humans, especially for vegan athletes with insufficient consumption of creatine and its precursors (arginine, methionine, and glycine).Moreover, by storing arginine, glycine, and methionine, creatine supplements enable other important metabolic pathways such as protein synthesis, nitric oxide, and glutathione production [368].
Finally, creatine supplementation reduces mitochondrial oxidative damage induced by exposure to neuro-/toxic substances [373].By enhancing the activity of antioxidant enzymes, creatine contributes to ROS and RNS elimination that benefits metabolism of amino acids susceptible to free radical oxidation such as arginine, glycine, and methionine [374].Health beneficial properties of creatine are summarized in Table 1.

Pyrroloquinoline quinone (PQQ)
PQQ is a well-known modulator of the energy-related metabolism and neuroprotector.Corresponding mechanisms reply on cellular signaling pathways and enhanced mitophagy and quality of mitochondrial function [375].Consequently, PQQ dietary supplementation decreases plasma levels of C-reactive protein and IL-6 as well as urinary methylated amines (e.g., trimethylamine N-oxide) [376] demonstrating also antiobesity effects and protection against obesity-related complications such as inflammation, non-alcoholic fatty liver disease, chronic kidney disease, and type 2 diabetes [377].
PQQ is not biosynthesized by mammals, but trace amounts have been detected in mouse and human tissues at picomolar to nanomolar levels.PQQ is abundant in nature and can be found in a variety of dietary sources, such as fermented soy beans (natto), tea, green peppers, parsley, kiwi fruit, and human milk [378].
PQQ serves as an accessory factor for lactate and possibly other dehydrogenases in oxidation of NADH to nicotinamide adenine dinucleotide (NAD +) [378,379].Therefore, the results of PQQ treatment resemble those of cellular NAD + such as maintaining mitochondriogenesis [380].
PQQ is involved in the synthesis of sirtuin-related proteins and by maintaining NAD + levels optimizes NAD + which is a cofactor and cosubstrate of sirtuin [380,381].
PQQ exposure prolongs the lifespan of models used in the study of ageing, improves cytokine response, and acts as a potent redox cycling agent that aids in the suppression of ROS [382].
It has been demonstrated that PQQ mitigates clinically relevant dysfunctions like ischemia, neurogenic losses, inflammation, and lipotoxicity [382].It provides neuroprotection and improves memory.In neurological injury, PQQ protects NMDA receptors [383,384].It is also reported that PQQ plays an important role in serum lipid metabolism, contributing to heart disease prevention [385].Furthermore, PQQ's cardioprotective effects in models of ischemia and reperfusion injury are comparable to those of metoprolol, a β1-selective adrenoceptor antagonist [386].The use of PQQ reduces jejunal mucosal inflammatory injury in experimental animals by blocking mechanisms related to nuclear factor-kappa B (NF-kB)-related pathways and improving the colonic microbiota disturbance caused by different agents [387].According to Naveed, inflammation of the gastrointestinal tract is strongly associated with the production of reactive oxygen species.By scavenging reactive oxygen species (ROS), PQQ acts as a protective agent.Furthermore, PQQ reduces the levels of C-reactive protein and interleukin-6 [388].

L-Carnosine
Carnosine (β-alanylhistidine, β-alanyl-L-histidine) is a dipeptide consisting of two amino acids (β-alanine and L-histidine) known to medical science since the year 1900  [389].Within the human body, and animal bodies as well, it is mostly contained in the skeletal muscle, brain, and heart [390][391][392].Carnosine is essential for the normal functioning of the cell.It restores the normal function of the cell and can extend its life via reducing the damage to telomeres [393,394].Carnosine effectively acts against processes that lead to deterioration of the condition or changes in cell structure, thus preventing the occurrence and development of various diseases.Many reactions of reactive oxygen species lead to the deterioration of the vital cell structures, including the ones within the mitochondria; in turn, the carnosine acting as highly effective antioxidant can counteract these damages to a big extent [390,391,395].Carnosine has an inhibitory effect on the process of glycation, thus preventing the occurrence of complications in diabetes-cataracts, atherosclerosis, reduction of kidney function, and other.Further, it prevents carbonylation of proteins leading to gradual disruption of their structure resulting in their complete destruction.Carnosine has the ability to chelate important bivalent metal ions such as copper and zinc [391,392].Finally, it contributes to elimination of toxic elements, therewith supporting systemic detoxification of human body and protecting against liver diseases [396].
In summary, L-carnosine-related pathways are linked to mitochondrial function; corresponding mechanisms are involved in protection against ageing; metabolic, cardiovascular, and ocular diseases; and neurodegeneration and involved in curative processes such as wound healing, which, if impaired, is considered a prestage to cascading pathologies [390-392, 395, 397].To this end, L-carnosine is beneficial for physical activities in gyms and outdoors contributing, therefore, to improved body fitness and high performance of professional athletes.Meat, fish, and eggs are the natural sources of L-carnosine; dietary supplements of L-carnosine are individually recommended depending on corresponding medical (e.g., impaired wound healing) and/or health conditions (e.g., regular body exercise and top athletes).
Octacosanol is a hydrophobic bioactive substance demonstrating several medicinal properties such as antifatigue, antihypoxia, antioxidant, anti-inflammatory, antitumor, and antiageing effects.Further important functions of octacosanol include modulation of the immune system and energy metabolism well-reflected in therapeutic benefits demonstrated for cardiovascular and cerebrovascular diseases, diabetes mellitus, and Parkinson's disease [399].It was also found that octacosanol extracted from leaves of Amazonian plant Sabicea grisea var.grisea has peripheral antinociceptive influence in mice, probably mediated by the alpha 2-adrenergic receptors.Contextually, octacosanol is considered for novel strategies for preventing pain and inflammation [400].
Octacosanol belongs to bioactive compounds effective against skeletal muscle diseases.Octacosanol can help resisting fatigue by modulating muscle-fiber-type transition via muscular energy metabolism.The mechanism is mediated by the Bcl3/TLRs/MAPK signaling pathway [398,401].To this end, octacosanol regulates several signaling pathways including AMPK, PI3K/Akt, and MAPK/ NF-κB highly relevant for the key physiological functions [399].
It is likely that octacosanol contents are insufficient in usually available diets and its supplementation as the valuable multi-faceted nutraceutical is desirable for health benefits and safe therapeutic approaches tailored to individualized patient profiles [402][403][404].

Pterostilbene
Pterostilbene (4-[(E)-2-(3,5-dimethoxyphenyl)ethen-1-yl] phenol, trans-3′,5′-dimethoxy-4-stilbenol) is a stilbenoid which is chemically close to the resveratrol but demonstrating an improved bioavailability [405,406].The most common natural sources of pterostilbene are blueberries, grape leaves, and vines [405,407,408].Pterostilbene demonstrates health beneficial pharmacological properties including antiinflammatory, antioxidant, antiapoptotic, neuroprotective, anticancer, antidiabetic, cardioprotective, and antiatherosclerotic ones-all linked to the mitochondrial physiology and protection including mitochondrial biogenesis, homeostasis, and rejuvenation under stress conditions [409].Pterostilbene is highly protective in suboptimal health conditions demonstrating strong therapeutic properties against ageing, obesity, chronic inflammation, and neurological (analgesics), cardiovascular, metabolic, and hematologic disorders [405,406].According to the most recent studies, pterostilbene may be superior to resveratrol in supporting mitochondrial biogenesis and regulating mitochondrial redox homeostasis, thereby preserving mitochondrial function, inhibiting cell apoptosis, and ameliorating oxidative stress-induced intestinal injury [410].Moreover, pterostilbene is capable to palliate negative health effects caused by mitochondrial mutations and to activate SIRT3 as well as its mitochondrial deacetylase function [411].Pterostilbene is commercially available as trans-pterostilbene in a dosage which usually corresponds to 50 mg of pterostilbene per capsule.

Alpha-lipoic acid
α-Lipoic acid (5-(1,2-dithiolan-3-yl)pentanoic acid, ALA, also thioctic acid) is an essential component of mitochondrial structure with a cofactor role in enzymatic reactions associated with aerobic pathways and coordination of energy metabolism [412].Although ALA is produced by each human cell, this amount is insufficient to cover all the requirements.ALA deficits are covered by diets rich in red meat, liver, heart, kidney, and some vegetables such as spinach broccoli, tomatoes, Brussels sprouts, potatoes, garden peas, and rice bran [413,414].ALA dietary supplements are commercially available and in combination with dihydrolipoic acid (DHALA) represent a potent antioxidant system capable of regenerating other antioxidants such as vitamin C, vitamin E, gluthathione, and coenzyme Q10-all essential for mitochondrial physiology and energy metabolism [413,415].

Catechins
Catechins are well-known scavengers of ROS and metal ion chelators inhibiting pro-oxidant enzymes while inducing antioxidant and detoxification enzymes and mitigating mitochondrial damage under stress overload.These are the key mechanisms underlying catechins's protective properties against oxidative stress implicated in accelerated ageing processes and associated pathologies including CVDs, neurodegeneration, cancers, and diabetes with cascading complications [416].Accumulated research data demonstrate specifically the central role of mitophagy modulation by catechins considered a new therapeutic option [417].
A number of foods and beverages naturally contain catechins, including green and black tea, coffee, berries, grapes, and wine [418].A number of catechin derivatives found in tea belong to the family of flavonoids called epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin chloride (ECC), and epicatechin chloride (EC) [418].The catechin content of green tea is much higher than that of black tea, and catechins are particularly abundant in green tea that has not been fermented.The antioxidant capacity of green tea leaves may vary depending on their variety and the place of origin [419].The health-promoting properties of green tea are mainly due to the presence of various beneficial polyphenols, particularly flavonols and flavanols.Catechin's antioxidant properties are attributed to its ability to chelate metal ions (specifically copper ions) in redox reactions and neutralize free oxygen radicals [419].
A number of human epidemiological and clinical studies have indicated that polyphenols found in green tea leaves have antitumor properties [420].Polyphenol's antitumor properties may be attributed to its suppression of cell division and activation of phase II antioxidant enzymes, such as superoxide dismutase, glutathione-Stransferase, and glutathione peroxidase and reductase [416].Green tea catechins have been reported to suppress aggressive metastatic cancer including prostate, colon, and lung malignancies [421][422][423].Various studies have indicated that polyphenols derived from green tea exhibit antitumor activity by modifying histones, micro-RNA, and DNA methylation [424].
A number of experimental studies have reported protective effects of (green tea) catechins against neurodegenerative processes including Alzheimer's disease.Corresponding protective mechanisms reply on antioxidative, anti-inflammatory, protein kinase C-related, and neurotransmissionrelated properties of catechins [425].
Considering catechins' numerous health-promoting properties, the inclusion of catechin-containing foods and drinks into the daily diet is highly recommended.

The vitamin B family
This group of vitamins are water-soluble coenzymes essential for a spectrum of metabolic pathways and functions at sub/cellular and organismal levels.To this end, mitochondrial health and functionality are compromized by a deficiency of any member of the B vitamin family [426]

Vitamin B 1 (thiamine)
The earliest and perhaps best acknowledged interrelationship between nutritional deficits and neurological impairments including cognitive deficits, encephalopathy, and dementia is related to the vitamin B 1 .The pathomechanisms rely on reductions in brain glucose metabolism and compromized mitochondrial health leading to cognitive deficits [427].
Thiamine is only produced by plants, microorganisms, and some fungi.Humans and animals acquire thiamine from nutrition, while intestinal bacteria produce insufficient amounts of it [428].
Dietary thiamine requirements vary based on age, gender, and lifestyle, with an adult requiring 1.1-1.5 mg/day.Plantderived foods such as enriched bread, whole wheat cereals, peas, beans, nuts, and brown rice contain thiamine (primarily in the form of thiamine monophosphate).It is also found in animal products (mainly in the form of thiamine pyrophosphate) such as pork, beef, and pork loin [428].Since the 1940s, processed cereal products (e.g., flour, bread, cereals) have been enriched with thiamin.During food processing, thiamin can be lost as a result of high temperatures [426].
Thiamine acts as an essential cofactor in central metabolic pathways such as in the citric acid cycle for the oxidative decarboxylation of the multi-enzyme branched-chain ketoacid dehydrogenase complexes [426].Further, thiamine exhibits significant antioxidant properties: as a ROS scavenger, thiamine neutralizes hydroxyl radicals (HO•) more effectively than hydroperoxyl radicals (HOO•), therewith protecting cells against a variety of toxic agents [429].However, under chronic stress overload, the level of thiamine, thiamine phosphates, and thiamine-dependent enzymes may get diminished leading to redox imbalance, e.g., seen in neurodegeneration [430].Thiamine deficiency reduces the activity of thiamine-dependent enzymes, notably α-ketoglutarate dehydrogenase complex, resulting in mitochondrial dysfunction, which leads to reduced activity of the tricarboxylic acid cycle in endothelial cells, astrocytes, and microglia.
Thiamine deficiency can be develop within 2-3 weeks of inadequate intake.Humans are therefore extremely susceptible to thiamine deficiency [431].In developed societies, chronic alcohol consumption is the most prevalent cause of acute thiamine deficiency.There are several reasons for this, including (I) poor intake, such as chronic alcoholism, a poor diet, or gastric bypass surgery; (II) insufficient absorption, including gastric bypass surgery, vomiting, neoplastic hyperplasia, malnutrition, and malabsorption syndrome; (III) increased loss, due to diarrhea, vomiting, hemodialysis, diuretic drug use, systemic illnesses, infections, and sepsis; and (IV) decreased utilization, such as pregnancy, lactation, decreased enzyme activity, and hyperthyroidism.Deficit of this nutrient in the human diet leads to impaired glucose metabolism, disruption of bioenergetic processes, mitochondrial dysfunction, lactic acidosis (the result of mitochondrial dysfunction of pyruvate dehydrogenase), suppressed DNA synthesis due to low transketolase activity and ribose-5-phosphate synthesis in the pentose phosphate pathway, and disrupted neurotransmitter synthesis.The most common pathology caused by a deficiency is beriberi, a cardiomyopathy characterized by edema and lactic acidosis, as well as Wernicke-Korsakoff syndrome and Wernicke's encephalopathy.Thiamine deficiency is involved in pathomechanisms of Alzheimer's, Parkinson's, and Huntington's diseases [426,428,432,433].

Vitamin B 2 (riboflavin)
Due to the relevance of riboflavin and thiamine to mitochondrial functionality, both vitamins currently undergo clinical evaluation for treatment of mitochondrial diseases.Corresponding strategies consider the use of agents enhancing electron transfer chain function.The medication cocktail comprises coenzyme Q10, riboflavin, thiamine, idebenone, and dichloroacetate [4].
Vitamin B 2 was first identified by Blyth in 1879 as a yellow pigment present in milk [434].It is a water-soluble and heat-stable vitamin degraded by the light exposure.Riboflavin can be found in a broad range of foods and natural sources, including milk, organ meats, eggs, fish, nuts, certain fruits and legumes, wild rice, mushrooms, dark green leafy vegetables, yeast, beer, cheese, and dietary supplements [434,435].Due to its limited absorption in humans, riboflavin must be obtained through a balanced diet to prevent riboflavinosis, which can result in symptoms such as cheilitis, sore tongue, and a scaly rash on the scrotum or vulva [436].Preclinical models demonstrated that supplementation with riboflavin significantly extends the lifespan and reproduction capacity [437].Additionally, riboflavin stimulates the synthesis of normal extracellular matrix and decreases reactive oxygen species levels in keratoconus [438].
Both flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) function as essential cofactors in numerous enzymatic reactions in all prokaryotic and eukaryotic cells modulating activities of superoxide dismutase, catalase and glutathione peroxidase, and cellular redox status, among others [437,439].FMN and FAD play an important role in bioenergetics, photochemistry, bioluminescence, redox homeostasis, chromatin remodeling, DNA repair, protein folding, and other processes [440] highly relevant for preventing a wide range of stress-related medical conditions including chronic inflammation, headaches, anemia, cancer, hyperglycaemia, hypertension, and diabetes, as summarized in Fig. 1.A riboflavin deficiency adversely impacts iron absorption, tryptophan metabolism, mitochondrial function, the gut, brain, and other vitamin metabolism such as vitamins B 6 and B 12 [435,441,442].

Vitamin B 3 (niacin)
Niacin is the natural NAD + booster required for the NADH synthesis to supply protons for oxidative phosphorylation, among others.As soon as nicotinamide enters the cells, it is primarily metabolized into NAD + , an electron carrier that is essential to the formation of ATP through mitochondrial respiration or glycolysis, and NADP + , which acts as a hydrogen donor in fatty acid or steroid synthesis or as a coenzyme in pentose synthesis in the pentose phosphate cycle.There are a variety of foods that contain niacin and nicotinamide, particularly fresh vegetables, milk, meat, whole or enriched grain cereal, and eggs [443].A large portion of uncooked foods contain NAD + and NADP + , which are hydrolyzed enzymatically to nicotinamide during cooking.Dietary niacin and nicotinamide are taken up from the stomach and intestine through sodium-dependent and passive diffusion.Tryptophan, a component of 1% of protein in the diet, can be turned endogenously into niacin via the kynurenine pathway and quinolinate [444].This provides most of the body's niacin demands.To convert tryptophan to niacin, vitamins B 2 and B 6 and iron are needed as cofactors.Subsequently, niacin and quinolinate are converted into nicotinic acid ribonucleotides and then into NAD + [443].Humans with severe nicotinamide deficiency develop pellagra (Italian "pelle agra"; "rough skin"), which is now most prevalent among malnourished alcoholics, but was formerly common in communities dependent upon corn-based diets.
A series of studies have linked altered nicotinamide levels with CNS deficits, Alzheimer's disease, Parkinson's disease, and Huntington's disease; nicotinamide treatment protects against neuronal injury, brain ischemia, and neurodegeneration and demonstrates behavioral recovery in animal models [445].
Further, several micronutrient deficiencies including nicotinamide, riboflavin, zinc, and magnesium have been associated with increased rates of esophageal cancer in China and Italy [446,447].There is also an increased risk of oral, gastric, and colon cancer associated with low dietary niacin intake, along with esophageal dysplasia.Based on analysis of a large Western population in the Malmo Diet and Cancer Study in Sweden, approximately 15-20% were deficient in niacin [448].Western populations are uncommonly affected by severe niacin deficiency that results in pellagra, but individuals at risk of pellagra may have suboptimal niacin intake, such as cancer patients and those exposed to genotoxic agents such as ionizing radiation, ultraviolet radiation, and alkylating agents [444].NAD + requirements are higher in tissues with high cellular turnover, such as breast, lung, and skin.As a result, they likely require higher doses of NAD + precursors when exposed to genotoxicity [449].

Vitamin B 6 (pyridoxal 5′-phosphate)
The fundamental role of the pyridoxal 5′-phosphate enzyme cofactor in human metabolism is well-established through more than 70 years of intensive research history in the field.Vitamin B 6 deficiency is associated with compromized mitochondrial health, CVDs (caused by impaired homocysteine metabolism and biosynthesis of vasomodulatory polyamines), epilepsy, and neuromuscular and neurological disorders [450].To this end, neurological disorders and visceral damage are functionally interrelated.The so-called polyglutamine (polyQ) toxicity leading to the neuronal loss and extensive injury of non-neuronal cells is mediated through mitochondria damage and includes the crucial role of the gut-brain axis and gut microbes in development and progression of neurological disorders.To this end, preclinical studies demonstrated mitochondrial protection by vitamin B 6 supplementation in fat bodies, indicating a promising preventive and therapeutic strategy for maintaining mitochondrial health and effective treatment of the polyQ-induced cellular toxicity [451].

Vitamin B 9 (folate)
Folate-based pathways enable activating and transferring one-carbon units for the biosynthesis of purines, thymidine, and methionine.Antifolates are important immunosuppressive and anticancer agents.Mitochondrial folate-associated enzymes are highly upregulated in quickly proliferating cancer cells that reflects the needs of mitochondria in folate-bound one-carbon units for a range of metabolic processes [452].For example, the loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2) leads to impaired mitochondrial translation-dependent on tRNA methylation and defective oxidative phosphorylation in human cells.Contextually, targeted antifolate treatments impair the respiratory chain and ATP production.The mechanism of an altered epigenetic control due to abnormal chromosomal and mitochondrial DNA methylation linked to the folate deficiency and hyperhomocysteinemia (Hhcy) is characteristic for several severe pathologies such as the leading cause of blindness in humans by proliferative diabetic retinopathy demonstrating a vicious circle in uncontrolled ROS production and irreversible damage to chromosomal and mitochondrial DNA [453].Contextually, the folate-based vitamin therapy targeting Hhcy is a promising 3PM approach in secondary DM care preventing associated pathologies [454,455].

Vitamin B 12 (cobalamin)
Mitochondria are the key players in synaptic neurotransmitter signaling providing ATP, mediating synthesis of bioactive molecules, buffering intracellular calcium, and modulating apoptotic and resilience pathways.To this end, cobalamin is considered an essential pillar among nutrients protecting mitochondrial function and neurotransmitter signaling in the neuronal circuits associated with cognitive and affective behaviors.The essential nutrients' set includes vitamin B 9 and B 12 , magnesium, ω3 fatty acids, and antioxidants (vitamin C and zinc) which collectively enhance neurocognitive function demonstrating therapeutic benefits in vulnerable groups predisposed to mood disorders and suicidal behavioral patterns [456].
Vitamin B 12 , a water-soluble vitamin, plays an important role in several biological processes including red blood cell production, DNA synthesis, nervous system function, and maintaining the structural integrity of chromosomes [457].In addition, as a cofactor, it aids in the synthesis of hormones, proteins, and lipids [458].Vitamin B 12 is present in several forms, including cyano-, methyl-, deoxyadenosyl-, and hydroxy-cobalamin.The cyano form, commonly used in supplements, is present in small amounts in food.The other forms of cobalamin can be transformed into the methyl-or 5-deoxyadenosyl forms that are necessary as cofactors for methionine synthase and L-methyl-malonyl-CoA mutase [459].
Vitamin B 12 is synthesized by specific bacteria in the gastrointestinal tract of animals and is then absorbed by the animal and incorporated into its tissues.Omnivores and carnivores, including humans, obtain B 12 from animal products like milk, cheese, and eggs.A rich source of cobalamin is the liver, followed by the kidney and heart.Neither natural nor synthetic forms of vitamin B 12 exist in plant sources.Seaweed and mushrooms are said to contain vitamin B 12 analogues that are inactive in humans [457,458].In the body, cobalamin binds to a protein called transcobalamin II and enters tissue through its receptors.Cobalamin contributes to two enzymatic reactions at the cellular level, methionine synthase and methyl-malonyl-co A mutase [458,459].
The vitamin B 12 plays a vital role in DNA synthesis and assists in maintaining the structural stability of key regions of chromosomes, such as centromeres and subtelomeric DNA.As a methyl donor, it is involved in the monocarbonic acid metabolic pathway and contributes to DNA methylation, which is particularly critical during embryogenesis and carcinogenesis.DNA methylation is catalyzed by DNA methyltransferases which transfer methyl groups from S-adenosylmethionine to cytosine.In addition to vitamin B 12 , other methyl group donors like pyridoxal 5′-phosphates and folate are needed as coenzymes for methyltransferase that remethylates homocysteine into methionine which is necessary for the methylation of several biological molecules, including DNA.So, B 12 can influence epigenetic mechanisms through its role in DNA methylation [460,461].
The main cause of vitamin B 12 deficiency is avoiding foods from animal origin, which are the only sources of this vitamin [460].Developing countries, the elderly, and vegetarians are at high risk of subclinical vitamin B 12 deficiencies.Blood levels of vitamin B 12 are not the definitive indicator of deficiency, since some people with a deficiency can display normal levels of vitamin B 12 [462].More health relevant way to measure vitamin B 12 activity is to determine blood levels of homocysteine and methylmalonic acid, which are elevated with vitamin B 12 deficiency.Clinical symptoms of vitamin B 12 deficiency are typically as an outcome of long-term and chronic malabsorption.The typical features of vitamin B 12 deficiency are illustrated in Fig. 2 [458].Medical conditions such as cardiovascular disease, cancers, compromized mental health, and adverse birth outcomes can also be caused by a B 12 deficiency [462,463].
Vitamins B 6 , B 9 , and B 12 Collectively, vitamins B 6 , B 9 , and B 12 are essential coenzymes of methyltransferase remethylating homocysteine into methionine and methylating biomolecules such as chrDNA and mtDNA (global epigenetic regulation); epigenetic modifications in mtDNA strongly contribute to the development of obesity, diabetes mellitus with cascading pathologies, cancers, CVDs, and neurodegeneration.To this end, altered methylation and hydroxymethylation patterns in mtDNA have been found in a series of preclinical and clinical studies considering tissues received from patients diagnosed with above-listed pathology [464].Environmental factors strongly influence mtDNA genome hydro/methylation level leading to compromized mitochondrial health, which can be effectively protected by vitamin supplementation algorithms tailored to individualized patient profiles.

Trehalose
In in vitro and in vivo analytical sets, trehalose administration was demonstrated to protect cells against cytotoxic effects and injury by activating autophagy and alleviating mitochondrial dysfunction [465,466].Cardiovascular and neuroprotective properties of trehalose based on restoring mitophagy and turnover of damaged mitochondria are considered for creating novel therapeutics [467,468].Trehalose is a naturally occurring disaccharide in a wide array of Fig. 2 Classical symptoms of vitamin B 12 deficiency [458] organisms including plants, bacteria, yeast, and fungi [469].A growing number of applications for trehalose are based on its bioprotective properties well-considered in the food, cosmetic, and pharmaceutical industries [470,471].Its potential therapeutic application is suggested to mitigate severity of neurodegenerative and cardiometabolic diseases [472] to suppress bone resorption and inflammation and to induce autophagy in relevant medical conditions [471].Specifically in diabetic patients: • Modulating the glucose signaling pathway to enhance insulin sensitivity • Modulating postprandial glucose levels to regulate glucose metabolism • Regulation of lipid metabolism by controlling postprandial insulin secretion • Improving activity of pancreatic islet by enhancing pancreatic beta cell function and inhibiting apoptotic processes involved in beta cell malfunction • Reducing free radical overload and improving insulin resistance by lowering oxidative stress • Inhibition of inflammatory responses through alleviation of inflammatory mediators By therapeutic application of trehalose may mitigate secondary complications [473].

Natural sets of nutraceuticals with multi-faceted beneficial effects
Accumulated data about health protective effects of nutraceuticals led to development of sets applicable to several medical conditions and consideration of natural sources rich in specific nutraceuticals as highlighted below.

DMG-gold as generalized promotor of metabolic and physical wellness
DMG-gold enhances mitochondrial energy metabolism and acts as an effective protector against stress overload and chronic inflammation.DMG-gold is composed of dimethylglycine (DMG), trimethylglycine (TMG), and vitamins B 1 , B 2 , B 3 , B 6 , and B 12 [426].Dimethylglycine boosts the body's antioxidant capacity by supplying glycine for glutathione synthesis [474,475].Furthermore, dimethylglycine, acting as a methyl donor, scavenges excessive free radicals and prevents oxidative stress [476].The antioxidant properties of B vitamins have also been proven to prevent adverse health effects of oxidative stress overload.According to the accumulated research data, administration of DMG-gold increases detoxifying enzyme activities (GST, NQO1) and glutathione levels, whereas decreasing oxidative stress and inflammation and improving mitochondrial homeostasis.Consequently, reduced serum levels of IL-6 and hepatic inflammatory parameters have been reported [477].

Ginkgo biloba
Per evidence, Ginkgo biloba extract (GBE) activates mitochondrial enzymes that assemble the electron transport system thereby improving mitochondrial respiration, increases production of ATP in neurons, protects brain against ageing, protects mtDNA against damage, and regulates membrane potentials and intramitochondrial Ca 2+ homeostasis [478,479].Although the GBE, specifically the flavonoids bilobalide and ginkgolides B and J, seem to possess the highest protection, it is difficult to discriminate between compounds with the most beneficial properties.Therefore, EGb761, a standardized leaf extract of Ginkgo biloba, is usually applied for treatments, when multi-faceted therapeutic effects are considered including scavenger, antioxidant, antibacterial, anti-inflammatory, antiallergic, and anticancer effects [479][480][481][482]. GBE is among the most frequently sold medicinal products in US health food stores [483] and used by traditional Chinese medicine for preventing neurodegenerative diseases, fever, coughs, and sputum production, as well as treating skin disorders, gonorrhea, toothaches, among others [484].Further, EGb761 applied together with grape seed skin extracts, quercetin, green tea, resveratrol, and bilberry extracts synergistically decrease diastolic blood pressure in hypertensive patients [481].Contextually, GBE protective effects were demonstrated for cardiovascular and retinal systems [479,482].Multi-faceted therapeutic effects of GBE are summarized in Fig. 3.

Propolis
Considering its immunomodulating, anti-inflammatory, antioxidant, anticancer, antibacterial, and antiviral properties, propolis has been proven to be effective in treating various diseases in primary and secondary care as summarized in Table 1.The key mechanisms rely on modulating mitochondrial bioactivities [491][492][493][494].
Due to its multi-faceted health beneficial effects, propolis is subjected to a numerous of studies in the pharmaceuticals and nutraceutical areas [495,496].Major constituents of propolis are flavonoids; phenolic compounds; polyphenols; terpenes; terpenoids; coumarins; steroids; amino acids; chalcones; essential oils; vitamin complexes A, B, C, and E; and minerals, including aluminum, sodium, potassium, calcium, copper, magnesium, iron, and zinc [495,497].Health beneficial properties of propolis are summarized in Table 2.

Saffron
An effective neuroprotectant saffron targets mitochondria and prevents mitochondrial dysfunction under clinically relevant stress conditions such as ischemia-reperfusion, demonstrating strong antiapoptotic effects [515,516].

Nutraceutical sets tailored to individualized patient profiles in primary care
Application of nutraceuticals is beneficial only if meeting needs at individual level.Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs.Based on the evidence presented above, here, we provide clinically relevant examples of frequent medical conditions, which per evidence require mitochondria-relevant supportive and protective measures as a holistic approach in primary and secondary care.The choice of nutraceutical sets has to be adapted to individualized patient profiles.In order to make the entire approach sound, the essentiality to apply machine learning (AI tool) for creating comprehensive individualized patient profiles followed by treatment algorithms tailored to the created profiles has to be clearly emphasized.

Case 1
-A 39-year-old female with characteristic symptoms and signs of the Flammer syndrome phenotype (FSF) (low BMI, low BP, frequently cold extremities, migraine with aura, sporadic arrhythmias, tinnitus, hard-to-heal wounds, shifted circadian rhythm, increased sensitivity towards stress and medication, meticulous personality,

Asthma
• Antiallergic, antiasthmatic, anti-inflammatory properties, due to inhibitory effects on activation of basophil and mast cells • Decreasing in frequency and severity of asthma attacks via decreasing inflammatory markers, such as TNF-α, IL-4, IL-5, and IL-6 [513,514] regular body exercise, etc.); family history of ischemic stroke and normal-tension glaucoma.-The functional link between FSF, systemic ischemic lesions, energy deficits, and compromized mitochondrial health is evidence-based and detailed in the peerreviewed scientific literature [11,[523][524][525][526][527][528].-Tear fluid analysis demonstrated a significantly decreased mitophagy level compared to the reference values in the corresponding group of age (the know-how of "3PMedicon GmbH" performing internationally validated tests) [529]; the methodology is described elsewhere [528].-Self-reported anxiety and chronic fatigue symptoms correlate well with the low mitophagy levels recorded.-Mitochondria-relevant nutraceuticals considered evidently supportive to stabilize health condition of the patient: CoQ 10 (increases ECT efficacy, mitigates oxidative stress and fatigue, protects mitochondrial health), vitamins B 1 and B 2 (increases ETC efficacy), melatonin (increases ETC efficacy, stabilizes sleep patterns, promotes cardio-and neuroprotection), quercetin (promotes mitophagy), L-arginine (stimulates NO production and vasodilatation), vitamin D 3 (promotes wound healing), and omega-3 fatty acid.-Additionally, Ginkgo biloba and green tea-both demonstrating multi-faceted mitochondrial and systemic protective effects-may be beneficial considering the abovelisted specific medical conditions.

Case 2
-A 61-year-old female, overweight, prediabetes type 2; family history of CVDs, chronic inflammatory disorders and cancers-all highly relevant to compromized mitochondrial health.-Self-reported psychosomatic issues.
-The functional link between overweight, metabolic syndrome, cascading complications on one hand, and, on the other hand, compromized mitochondrial health is evidence-based and detailed in the peer-reviewed scientific literature [1,2].-Tear fluid analysis demonstrated a significantly increased mitophagy level compared to the reference values in the corresponding group of age (the know-how of "3PMedicon GmbH" performing internationally validated tests) [529]; the methodology is described elsewhere [528].-Mitochondria-relevant nutraceuticals are considered supportive to stabilize health condition of the patient: CoQ 10 (anti-inflammatory effects, increases ECT efficacy, mitigates oxidative stress, protects mitochondrial health under pre/diabetic medical conditions), Ketogenic diet in combination with the L-carnitine supplement (promotes ß-oxidation pathways, protects against cascading complications associated with pre/diabetes), resveratrol (strong anti-inflammatory and anticancer effects), and either curcumin or silibinin (strong anti-inflammatory and anticancer protection).-Further recommendations: couched body exercise to decrease body weight and to increase mitochondrial mass and ATP production; probiotic intake, because gut microbiota has an essential role in the prevention of and protection against both the metabolic disorder and cancer predisposition [530].

Case 3
-A 55-year-old male, sedentary lifestyle, overweight, obstructive sleep apnea (OSA); family history: cardiovascular, malignant, and neurodegenerative disorders-all are highly relevant to compromized mitochondrial health.-Self-reported stress overload and chronic fatigue.
-The functional link between sedentary lifestyle and overweight with cascading complications on one hand and, on the other hand, compromized mitochondrial health is evidence-based and detailed in the peer-reviewed scientific literature [1,2].Per evidence, OSA is associated with elevated homocysteine levels in blood [531]; moreover, the severity of OSA is significantly associated with elevated homocysteine levels in patients with ischaemic stroke [532].-Tear fluid analysis indicated an extremely decreased mitophagy level with a potential to mitochondrial burnout compared to the reference values in the corresponding group of age (the know-how of "3PMedicon GmbH" performing internationally validated tests) [529]; the methodology is described elsewhere [528] that correlates well with the imbalanced stress overload and symptoms of chronic fatigue reported.-Mitochondria-relevant nutraceuticals considered evidently supportive to stabilize health condition of the patient: CoQ 10 (anti-inflammatory effects, increases ECT efficacy, mitigates oxidative stress, protects mitochondrial health), Ketogenic diet in combination with L-carnitine supplement (promotes ß-oxidation pathways, protects against cascading complications related to overweight), quercetin (promotes mitophagy), ginsenosides (protective against cancer, diabetes, CVD and, neurodegeneration; mitochondria-protective effects), and vitamins B 12 , B 6 , and B 9 (remethylation of homocysteine into methionine, epigenetic control, and protection of mtDNA and chrDNA).-Additionally, Ginkgo biloba and green tea-both demonstrating multi-faceted mitochondrial and systemic protective effects-may be beneficial considering the abovelisted specific medical conditions.-Further recommendations: couched body exercises to decrease body weight and to increase mitochondrial mass and ATP production; probiotic intake, because gut microbiota has an essential role in the prevention of and protection against CVDs and cancer predisposition [530].

Innovative concepts of prehabilitation and rehabilitation approaches based on application of mitochondria-relevant nutraceuticals-clinically relevant examples for secondary care
In the development and progression of critical illnesses as well as in stabilizing health condition and healing of the affected person, mitochondria play the central multi-faceted role including energy metabolism, cell signaling, and regulation of gene expression and cellular calcium levels as well as activation either repair mechanisms or cell death pathways in case of irreversible damage [533].To this end, damaged mitochondria generate signals, most notably released mtDNA acting systemically as the danger-associated molecular patterns throughout the body [533].Therefore, to a great extent, physiologic homeostasis and intact functionality of mitochondrial populations are decisive at the organismal level for individual outcomes of life-threatening illnesses.Keeping these facts in mind, innovative concepts of prehabilitation and rehabilitation approaches based on application of mitochondrial health supportive nutraceuticals are clinically relevant for several medical conditions exemplified below.

Coronary artery bypass graft surgery
Coronary artery disease causes systemic ischemia and extensive cell death.Revascularization by coronary artery bypass grafting effectively relieves symptoms and decreases mortality in affected patient cohort.However, mitochondrial populations become extensively damaged by ischemia-reperfusion generating excessive ROS and inflammation coupled with compromized metabolic activity and highly increased oxidative stress throughout the body causing systemic toxicity and irreversible organ damage [534].Contextually, mitochondria-specific protective measures by individualized sets of nutraceutics applied prior to the surgery (prehabilitation) and after the revascularization (rehabilitation) may have enormous health beneficial effects as supported by accumulated evidence [535][536][537].

Ischemic stroke
Mitochondrial dysfunction is the key contributor to the cerebral ischemia-reperfusion damage, and mitochondrial population is an important drug target for treatments of ischemic stroke.Contextually, technological solutions for the mitochondrial transfer by stem cells and delivery of mitochondria-containing extracellular vesicles for ischemic stroke treatments are extensively under consideration [538,539].Further, mitophagy was proposed as a specific therapeutic target to advance treatments of ischemic stroke [540].
Collectively, these findings indicate that the concept of mitochondria-based IS rehabilitation utilizing nutraceuticals targeted to specific mitochondrial functions may have enormous cost-effective benefits to health of affected individuals.

Treated cancers
A mounting research data demonstrate that chemotherapy introduces a systemic damage to mitochondrial populations throughout the body of treated cancer patients.For example, treatments usually applied to breast cancer are associated with a range of neurotoxic symptoms including pain, chronic fatigue, and cognitive impairments.Even after the treatment completion, these symptoms remain in a significant subset of survivors.Mitochondrial stress, damage, and impairments coupled with neuroinflammation considered the mechanistic pathways underlying neurotoxic symptoms [541].Besides chronic fatigue, the health adverse effects are further reflected in muscle weakness that can be wellillustrated with breast and prostate patients treated with doxorubicin [542].
To restore mitochondrial functions and to mitigate DOXinduced fatigue, preclinical studies utilized treadmill exercises in a rat model demonstrating beneficial effects resulting in alleviation of muscle weakness and central fatigue.On the other hand, accumulated research data demonstrate that the ROS production significantly elevated by acute body exercises causes whole-body oxidative stress highly relevant for mitochondrial and multi-organ damage [543].Indeed, recently performed study demonstrates significantly reduced exercise capacity typical for early-stage breast cancer patients treated with chemotherapy [544].This finding strongly supports the conclusion that in order to be beneficial, body exercise needs algorithms elaborated individually for cancer-treated patients, accompanied with effective support and monitoring of mitochondrial functions.
Contextually, innovative concepts of prehabilitation (prior to chemotherapeutic and irradiation treatments) and rehabilitation (after the treatment completion) elaborated for cancer patient utilizing mitochondria-supportive nutraceuticals are of great clinical relevance in secondary care.In consensus, the Mediterranean diet (MedDiet) in which dietary patterns are known as promoting energy metabolism was recently demonstrated as feasible to attenuate cancer-related fatigue among patients undergoing chemotherapy and irradiation; the efficacy is particularly remarkable for patients recorded with lower MedDiet scores at baseline [545].