Abstract
This study aimed to determine the effects of mitotherapy on learning and memory and hippocampal kynurenine (Kyn) pathway, mitochondria function, and dendritic arborization and spines density in aged rats subjected to chronic mild stress. Twenty-eight male Wistar rats (22 months old( were randomly divided into Aged, Aged + Mit, Aged + Stress, and Aged + Stress + Mit groups. Aged rats in the stress groups were subjected to different stressors for 28 days. The Aged + Mit and Aged + stress + Mit groups were treated with intracerebroventricular injection (10 µl) of fresh mitochondria harvested from the young rats’ brains, and other groups received 10 µl mitochondria storage buffer. Spatial and episodic-like memories were assessed via the Barnes maze and novel object recognition tests. Indoleamine 2,3-dioxygenase (IDO) expression and activity, Kyn, Tryptophan (TRY), ATP levels, and mitochondrial membrane potential (MMP) were measured in the hippocampus region. Golgi-Cox staining was also performed to assess the dendritic branching pattern and dendritic spines in the hippocampal CA1 subfield. The results showed that mitotherapy markedly improved both spatial and episodic memories in the Aged + Stress + Mit group compared to the Aged + Stress. Moreover, mitotherapy decreased IDO protein expression and activity and Kyn levels, while it increased ATP levels and improved MMP in the hippocampus of the Aged + Stress + Mit group. Besides, mitotherapy restored dendritic atrophy and loss of spine density in the hippocampal neurons of the stress-exposed aged rats. These findings provide evidence for the therapeutic effect of mitotherapy against stress-induced cognitive deterioration in aged rats by improving hippocampal mitochondrial function and modulation of the Kyn pathway.
Graphical abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Alexander JF, Seua AV, Arroyo LD et al (2021) Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics 11:3109–3130. https://doi.org/10.7150/THNO.53474
Amaral M, Outeiro TF, Scrutton NS, Giorgini F (2013) The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J Mol Med 91:705–713. https://doi.org/10.1007/s00109-013-1046-9
Antunes M, Biala G (2012) The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process 13:93–110. https://doi.org/10.1007/s10339-011-0430-z
Azam S, Haque ME, Balakrishnan R et al (2021) The ageing brain: molecular and cellular basis of neurodegeneration. Front Cell Dev Biol 9:2120. https://doi.org/10.3389/fcell.2021.683459
Banagozar Mohammadi A, Torbati M, Farajdokht F et al (2019) Sericin alleviates restraint stress induced depressive- and anxiety-like behaviors via modulation of oxidative stress, neuroinflammation and apoptosis in the prefrontal cortex and hippocampus. Brain Res 1715:47–56. https://doi.org/10.1016/j.brainres.2019.03.020
Bansal Y, Kuhad A (2016) Mitochondrial dysfunction in depression. Curr Neuropharmacol 14:610–618. https://doi.org/10.2174/1570159x14666160229114755
Bayram-Weston Z, Olsen E, Harrison DJ et al (2016) Optimising Golgi-Cox staining for use with perfusion-fixed brain tissue validated in the zQ175 mouse model of Huntington’s disease. J Neurosci Methods 265:81–88. https://doi.org/10.1016/j.jneumeth.2015.09.033
Behl T, Kaur I, Sehgal A et al (2021) The footprint of kynurenine pathway in neurodegeneration: janus-faced role in parkinson’s disorder and therapeutic implications. Int J Mol Sci 22:6737. https://doi.org/10.3390/ijms22136737
Bettio LEB, Rajendran L, Gil-Mohapel J (2017) The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 79:66–86. https://doi.org/10.1016/j.neubiorev.2017.04.030
Bobkova NV, Zhdanova DY, Belosludtseva NV et al (2021) Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice. Exp Biol Med. https://doi.org/10.1177/15353702211056866
Bordelon YM, Chesselet MF, Nelson D et al (1997) Energetic dysfunction in quinolinic acid-lesioned rat striatum. J Neurochem 69:1629–1639. https://doi.org/10.1046/j.1471-4159.1997.69041629.x
Cabral JCC, Veleda GW, Mazzoleni M et al (2016) Estresse e Reserva Cognitiva como determinantes independentes para o desempenho neuropsicológico de idosos saudáveis. Cienc e Saude Coletiva 21:3499–3508. https://doi.org/10.1590/1413-812320152111.17452015
Caicedo A, Aponte PM, Cabrera F et al (2017) Artificial mitochondria transfer: current challenges, advances, and future applications. Stem Cells Int. https://doi.org/10.1155/2017/7610414
Carrier M, Šimončičová E, St-Pierre MK et al (2021) Psychological stress as a risk factor for accelerated cellular aging and cognitive decline: the involvement of microglia-neuron crosstalk. Front Mol Neurosci. https://doi.org/10.3389/fnmol.2021.749737
Chavez-Valdez R, Martin LJ, Flock DL, Northington FJ (2012) Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience 219:192–203. https://doi.org/10.1016/j.neuroscience.2012.05.002
Chistiakov DA, Sobenin IA, Revin VV et al (2014) Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 238463. https://doi.org/10.1155/2014/238463
Comijs HC, van den Kommer TN, Minnaar RWM et al (2011) Accumulated and differential effects of life events on cognitive decline in older persons: depending on depression, baseline cognition, or ApoE epsilon4 status? J Gerontol B Psychol Sci Soc Sci 66(Suppl 1):i111–i120. https://doi.org/10.1093/geronb/gbr019
Devine MJ, Kittler JT (2018) Mitochondria at the neuronal presynapse in health and disease. Nat Rev Neurosci 19:63–80. https://doi.org/10.1038/nrn.2017.170
Dickstein DL, Weaver CM, Luebke JI, Hof PR (2013) Dendritic spine changes associated with normal aging. Neuroscience 251:21–32. https://doi.org/10.1016/j.neuroscience.2012.09.077
Driscoll I, Hamilton DA, Petropoulos H et al (2003) The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex 13:1344–1351. https://doi.org/10.1093/cercor/bhg081
Fallahi S, Babri S, Farajdokht F et al (2019) Neuroprotective effect of ghrelin in methamphetamine-treated male rats. Neurosci Lett. https://doi.org/10.1016/j.neulet.2019.134304
Fernandez A, Meechan DW, Karpinski BA et al (2019) Mitochondrial dysfunction leads to cortical under-connectivity and cognitive impairment. Neuron 102:1127–1142e3. https://doi.org/10.1016/j.neuron.2019.04.013
Ghaffari-Nasab A, Badalzadeh R, Mohaddes G, Alipour MR (2021) Young plasma administration mitigates depression-like behaviours in chronic mild stress-exposed aged rats by attenuating apoptosis in prefrontal cortex. Exp Physiol 106:1621–1630. https://doi.org/10.1113/EP089415
Ghaffari-Nasab A, Badalzadeh R, Mohaddes G et al (2022) Young plasma induces antidepressant-like Effects in aged rats subjected to chronic mild stress by suppressing Indoleamine 2,3-Dioxygenase enzyme and kynurenine pathway in the Prefrontal Cortex. Neurochem Res 47:358–371. https://doi.org/10.1007/s11064-021-03440-9
Gong Y, Chai Y, Ding JH et al (2011) Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci Lett 488:76–80. https://doi.org/10.1016/j.neulet.2010.11.006
Heisler JM, O’Connor JC (2015) Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory. Brain Behav Immun 50:115–124. https://doi.org/10.1016/j.bbi.2015.06.022
Hidalgo V, Pulopulos MM, Puig-Perez S et al (2015) Acute stress affects free recall and recognition of pictures differently depending on age and sex. Behav Brain Res 292:393–402. https://doi.org/10.1016/j.bbr.2015.07.011
Hosseini L, Farokhi-Sisakht F, Badalzadeh R et al (2019) Nicotinamide mononucleotide and melatonin alleviate aging-induced cognitive impairment via modulation of mitochondrial function and apoptosis in the Prefrontal Cortex and Hippocampus. Neuroscience 423:29–37. https://doi.org/10.1016/j.neuroscience.2019.09.037
Jaeger J, Berns S, Uzelac S, Davis-Conway S (2006) Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 145:39–48. https://doi.org/10.1016/j.psychres.2005.11.011
Javani G, Babri S, Farajdokht F et al (2022) Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats. Mech Ageing Dev 202:111632. https://doi.org/10.1016/j.mad.2022.111632
Kaim G, Dimroth P (1999) ATP synthesis by F-type ATP synthase is obligatorily dependent on the transmembrane voltage. EMBO J 18:4118–4127. https://doi.org/10.1093/emboj/18.15.4118
Kambe Y (2015) Potential involvement of mitochondrial dysfunction in major depressive disorder: recent evidence. Arch Depress Anxiety 1:019–028. https://doi.org/10.17352/2455-5460.000004
Khacho M, Clark A, Svoboda DS et al (2017) Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis. Hum Mol Genet 26:3327–3341. https://doi.org/10.1093/hmg/ddx217
Kim EJ, Pellman B, Kim JJ (2015) Stress effects on the hippocampus: a critical review. Learn Mem 22:411–416. https://doi.org/10.1101/lm.037291.114
Knoops AJG, Gerritsen L, van der Graaf Y et al (2010) Basal hypothalamic pituitary adrenal Axis activity and hippocampal volumes: the SMART-Medea Study. Biol Psychiatry 67:1191–1198. https://doi.org/10.1016/j.biopsych.2010.01.025
La Torre D, Dalile B, de Loor H et al (2021) Changes in kynurenine pathway metabolites after acute psychosocial stress in healthy males: a single-arm pilot study. Stress 24:920–930. https://doi.org/10.1080/10253890.2021.1959546
Lee T, Jarome T, Li SJ et al (2009) Chronic stress selectively reduces hippocampal volume in rats: a longitudinal magnetic resonance imaging study. NeuroReport 20:1554–1558. https://doi.org/10.1097/WNR.0b013e328332bb09
Ma H, Jiang T, Tang W et al (2020) Transplantation of platelet-derived mitochondria alleviates cognitive impairment and mitochondrial dysfunction in db/db mice. Clin Sci 134:2161–2175. https://doi.org/10.1042/CS20200530
Maggio N, Segal M (2010) Corticosteroid regulation of synaptic plasticity in the hippocampus. ScientificWorldJournal 10:462–469. https://doi.org/10.1100/tsw.2010.48
McEwen BS, Bowles NP, Gray JD et al (2015) Mechanisms of stress in the brain. Nat Neurosci 18:1353–1363. https://doi.org/10.1038/nn.4086
Messaoud A, Mensi R, Douki W et al (2019) Reduced peripheral availability of tryptophan and increased activation of the kynurenine pathway and cortisol correlate with major depression and suicide. World J Biol Psychiatry 20:703–711. https://doi.org/10.1080/15622975.2018.1468031
Mor A, Tankiewicz-Kwedlo A, Krupa A, Pawlak D (2021) Role of kynurenine pathway in oxidative stress during neurodegenerative disorders. Cells 10:1603. https://doi.org/10.3390/cells10071603
Nascimento-Dos-santos G, De-Souza-ferreira E, Linden R et al (2021) Mitotherapy: unraveling a promising treatment for disorders of the central nervous system and other systemic conditions. Cells 10:1827. https://doi.org/10.3390/cells10071827
Nicholls DG (2004) Mitochondrial membrane potential and aging. Aging Cell 3:35–40. https://doi.org/10.1111/j.1474-9728.2003.00079.x
Nitzan K, Benhamron S, Valitsky M et al (2019) Mitochondrial transfer ameliorates cognitive deficits, neuronal loss, and gliosis in Alzheimer’s Disease mice. J Alzheimers Dis 72:587–604. https://doi.org/10.3233/JAD-190853
Olesen MA, Torres AK, Jara C et al (2020) Premature synaptic mitochondrial dysfunction in the hippocampus during aging contributes to memory loss. Redox Biol 34:101558. https://doi.org/10.1016/j.redox.2020.101558
Park A, Oh M, Lee SJ et al (2021) Mitochondrial transplantation as a novel therapeutic strategy for mitochondrial diseases. Int J Mol Sci. https://doi.org/10.3390/ijms22094793
Prenderville JA, Kennedy PJ, Dinan TG, Cryan JF (2015) Adding fuel to the fire: the impact of stress on the ageing brain. Trends Neurosci 38:13–25. https://doi.org/10.1016/j.tins.2014.11.001
Salehpour F, Farajdokht F, Mahmoudi J et al (2019) Photobiomodulation and coenzyme Q10 treatments attenuate cognitive impairment associated with model of transient global brain ischemia in artificially aged mice. Front Cell Neurosci 13:1–17. https://doi.org/10.3389/fncel.2019.00074
Sas K, Szabó E, Vécsei L (2018) Mitochondria, oxidative stress and the kynurenine system, with a focus on ageing and neuroprotection. Molecules 23(1):191
Schloesser A, Esatbeyoglu T, Piegholdt S et al (2015) Dietary tocotrienol/γ-cyclodextrin complex increases mitochondrial membrane potential and ATP concentrations in the brains of aged mice. Oxid Med Cell Longev. https://doi.org/10.1155/2015/789710
Soetanto A, Wilson RS, Talbot K et al (2010) Association of anxiety and depression with microtubule-associated protein 2- and synaptopodin-immunolabeled dendrite and spine densities in hippocampal CA3 of older humans. Arch Gen Psychiatry 67:448–457. https://doi.org/10.1001/archgenpsychiatry.2010.48
Song L, Che W, Min-wei W et al (2006) Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Behav 83:186–193. https://doi.org/10.1016/j.pbb.2006.01.004
Sorgdrager FJH, van Der Ley CP, van Faassen M et al (2020) The effect of tryptophan 2,3-dioxygenase inhibition on kynurenine metabolism and cognitive function in the APP23 mouse model of Alzheimer’s Disease. Int J Tryptophan Res 13:1178646920972657. https://doi.org/10.1177/1178646920972657
Sousa N, Lukoyanov NV, Madeira MD et al (2000) Erratum: reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement (Neurosicience 97:2 (253–266) PII: S0306452200000506). Neuroscience 101:483. https://doi.org/10.1016/S0306-4522(00)00465-6
Stone TW, Darlington LG (2013) The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol 169:1211–1227. https://doi.org/10.1111/bph.12230
Sugrue MM, Tatton WG (2001) Mitochondrial membrane potential in aging cells. Neurosignals 10:176–188. https://doi.org/10.1159/000046886
Sussams R, Schlotz W, Clough Z et al (2020) Psychological stress, cognitive decline and the development of dementia in amnestic mild cognitive impairment. Sci Rep 10:1–11. https://doi.org/10.1038/s41598-020-60607-0
Todorova V, Blokland A (2016) Mitochondria and synaptic plasticity in the mature and aging nervous system. Curr Neuropharmacol 15:166–173. https://doi.org/10.2174/1570159x14666160414111821
Tomtheelnganbee E, Sah P, Sharma R (2022) Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions. Biogerontology 16:1–24. https://doi.org/10.1007/s10522-022-09978-7
Wang Y, Ni J, Gao C et al (2019) Mitochondrial transplantation attenuates lipopolysaccharide-induced depression-like behaviors. Prog Neuropsychopharmacol Biol Psychiatry 93:240–249. https://doi.org/10.1016/j.pnpbp.2019.04.010
Yin F, Sancheti H, Patil I, Cadenas E (2016) Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med 100:108–122. https://doi.org/10.1016/j.freeradbiomed.2016.04.200
Zhao Z, Yu Z, Hou Y et al (2020) Improvement of cognitive and motor performance with mitotherapy in aged mice. Int J Biol Sci 16:849–858. https://doi.org/10.7150/ijbs.40886
Zhao J, Qu D, Xi Z et al (2021) Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF. Transl Res 235:102–114. https://doi.org/10.1016/j.trsl.2021.03.017
Acknowledgements
This study has been derived from the Ph.D. dissertation of Mrs. Gonja Javani titled “Mitochondrial Transplantation Improves Anxiety- and Depression-like Behaviors in Aged Stress-exposed Rats.“ The financial support for this study was provided by the Neurosciences Research Center of Tabriz University of Medical Sciences.
Funding
This work was supported by the Neurosciences Research Center of Tabriz University of Medical Sciences (Grant Number: 63881).
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation and data collection and analysis were performed by GJ, FF, AG-N, and GM. The first draft of the manuscript was written by GJ, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors have no competing interests to declare that are relevant to the content of this article.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Javani, G., Babri, S., Farajdokht, F. et al. Mitotherapy restores hippocampal mitochondrial function and cognitive impairment in aged male rats subjected to chronic mild stress. Biogerontology 24, 257–273 (2023). https://doi.org/10.1007/s10522-022-10014-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-022-10014-x