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Modulation of mitochondrial physiology in neuroprotection and neurotoxicity

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As the primary producers of adenosine triphosphate (ATP) mitochondria are central in the maintenance of cellular bioenergetic state. Moreover, these organelles provide an important source of reactive species, which act in both physiological and pathological contexts. Mitochondria can also undergo fusion (when two mitochondria form one mitochondrion) and fission (when one mitochondrion divides into two mitochondria). These processes may be viewed as part of the adaptation to stress since their major aim is to maintain functional mitochondria. During mitochondrial biogenesis (also called mitogenesis), new mitochondria are generated in cells under specific conditions. On the other hand, mitophagy is a physiological route for the elimination of mitochondria. Disorders in the mitochondrial physiology can potentially lead to cell death. This Topical Collection focuses on the involvement of mitochondria in different scenarios, as well as on the impact of the modulation of mitochondrial physiology-related parameters on response to stress and on cell fate.

Hei et al. (2023) investigated the effects of rapamycin on the brain damage induced by middle cerebral artery occlusion (MCAO) in diabetic rats. The authors found that rapamycin blocked MCAO-induced mitochondrial fission in the diabetic group, and attenuated brain damage.

Brasil et al. (2023a) tested whether isoorientin, a natural flavone, could prevent mitochondrial impairment caused by methylglyoxal in the SH-SY5Y cell line. They found that isoorientin prevented mitochondrial dysfunction by stimulating the synthesis of glutathione (GSH) through the AMPK-PI3K/Act pathway. The same research group (Brasil et al., 2023b) also demonstrated that isothiocyanate sulforaphane prevented mitochondrial impairment and neuroinflammation in both human neuroblastoma SH-SY5Y and mouse microglial BV-2 cells exposed to different chemical stressors.

The work of Hammerschmidt et al. (2023) investigated whether β-cyclodextrin could ameliorate mitochondrial impairment in the fibroblasts obtained from patients suffering from Niemann-Pick C1 (NPC1) disease, a disease characterized by the accumulation of cholesterol and other lipids in different cellular compartments. The authors observed that nanoparticles containing β-cyclodextrin decreased the levels of cholesterol in the NPC1 fibroblasts. The combination of these nanoparticles with N-acetylcysteine and coenzyme Q10 efficiently reduced the production of superoxide radical (O2-•) by mitochondria, suggesting a promising therapeutic strategy for NPC1 disease.

Jacques et al. (2023) examined redox and bioenergetic alterations in an in vitro experimental model of type II mucopolysaccharidosis using the iduronate-2-sulfatase (IDS)-deficient human embryonic kidney 293 (HEK 293) cells. The authors also tested whether genistein and coenzyme Q10 would be able to attenuate the molecular and cellular impairments in this experimental design. No alterations in mitochondrial function was found; however, redox dysfunctions were observed. The administration of either genistein or coenzyme Q10 alleviated the oxidative stress in the IDS-deficient HEK 293 cells. This is an important step towards the development of in vitro experimental models for research focusing on inborn errors of metabolism.

The balance between mitochondrial fission and fusion, as well as mitophagy, seems to play a role in the development of seizures. Fang et al. (2023) investigated the impact of modulating cerebral mitochondrial fission in an experimental model of juvenile rat epilepsy induced by pentatetrazol (PTZ). The authors found that inhibition of mitochondrial fission by Mdivi-1 decreased seizure attacks and improved cognition in the rats exposed to PTZ. Mdivi-1 also exerted mitochondria-related anti-apoptotic effect by reducing the levels of activated caspase-3 in the hippocampi of PTZ-exposed rats. Thus, the modulation of mitochondrial fission may be a potential therapeutic target for epilepsy.

Shah et al. (2023) discuss potential role of sulforaphane in modulating signaling pathways associated with the autism spectrum disorders (ASD). Sulforaphane is a potent inducer of the transcription factor Nrf2, a major modulator of redox biology in human cells. Nrf2 coordinates the expression of several cytoprotective enzymes whose products may promote mitochondrial protection and anti-inflammatory effects, among other actions.

Varma et al. (2023), also in the ASD research field, suggest that niclosamide, an antihelminthic drug, could be useful in the treatment of ASD due to its potent anti-inflammatory activity. Niclosamide also protects mitochondrial by inhibiting the Erk-associated signaling pathway.

Overall, this Topical Collection demonstrates that the modulation of mitochondrial physiology may play an important role in the prevention and/or treatment of several conditions that affect the homeostasis of brain cells. Moreover, potential therapeutic strategies are proposed and discussed.

Editors

  • Marcos Roberto de Oliveira (Federal University of Mato Grosso) Marcos Roberto de Oliveira (Federal University of Mato Grosso)

    Marcos Roberto de Oliveira (Federal University of Mato Grosso)

    Professor Marcos Roberto de Oliveira, PhD investigates the potential role of natural molecules in the promotion of mitochondrial protection in human cells in different experimental models. He published over 100 articles and edited scientific books in the field. Dr. de Oliveira is a member of the Editorial Board of Metabolic Brain Disease.

Articles (8 in this collection)