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In rodent models, CSIS produces two phenotypes: CSIS-susceptible, which develop depressive- and anxiety-like behaviors, and CSIS-resilient, which maintain normal behavior despite stress. However, the biological mechanisms underlying resilience to stress remain elusive. Mitochondria, as central regulators of neuronal energy metabolism and redox balance, are potential mediators of stress susceptibility and resilience. This review summarizes comparative proteomic analyses of hippocampal nonsynaptic mitochondria (NSM) and synaptosome-enriched mitochondria from CSIS-susceptible and CSIS-resilient rats along with controls. In NSM of resilient rats relative to susceptible rats, remodeling enhanced energy production, limited reactive oxygen species, stabilized phosphate transport, and promoted removal of damaged components. Compared with controls, these changes optimized energy production, and selectively downregulated oxidative stress-promoting proteins. Conversely, synaptosome-enriched mitochondria from resilient rats showed downregulation of proteins related to synaptic energy metabolism and redox balance relative to CSIS-susceptible rats, but demonstrated upregulation of bioenergetic and antioxidant enzymes, molecular chaperones, and neuroprotective factors compared with controls. These proteomic signatures both highlight mitochondrial adaptability in promoting stress resilience and identify mitochondria as promising targets for the development of novel antidepressant therapies.<\/jats:p>","DOI":"10.3390\/biom15101358","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T07:46:49Z","timestamp":1758786409000},"page":"1358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Proteomic Signatures of Hippocampal Nonsynaptic and Synaptosome-Enriched Mitochondria in Rats Resilient to Chronic Social Isolation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7828-4168","authenticated-orcid":false,"given":"Dragana","family":"Filipovi\u0107","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Endocrinology, VIN\u010cA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph W.","family":"Turck","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, KIZ\/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences Kunming, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1037\/0882-7974.21.1.140","article-title":"Loneliness as a Specific Risk Factor for Depressive Symptoms: Cross-Sectional and Longitudinal Analyses","volume":"21","author":"Cacioppo","year":"2006","journal-title":"Psychol. Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41398-022-02178-4","article-title":"The Effects of Social Isolation Stress and Discrimination on Mental Health","volume":"12","author":"Brandt","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/hsc.12311","article-title":"Social Isolation, Loneliness and Health in Old Age: A Scoping Review","volume":"25","author":"Courtin","year":"2017","journal-title":"Health Soc. Care Community"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1515\/revneuro-2016-0072","article-title":"Hippocampal BDNF in Physiological Conditions and Social Isolation","volume":"28","author":"Zaletel","year":"2017","journal-title":"Rev. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1146\/annurev-psych-010814-015240","article-title":"The Neuroendocrinology of Social Isolation","volume":"66","author":"Cacioppo","year":"2015","journal-title":"Annu. Rev. Psychol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s11055-022-01297-1","article-title":"Effects of Social Isolation on the Development of Anxiety and Depression-Like Behavior in Model Experiments in Animals","volume":"52","author":"Grigoryan","year":"2022","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.bbr.2008.10.036","article-title":"The Effect of Chronic Fluoxetine on Social Isolation-Induced Changes on Sucrose Consumption, Immobility Behavior, and on Serotonin and Dopamine Function in Hippocampus and Ventral Striatum","volume":"198","author":"Brenes","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.biopha.2018.05.086","article-title":"Neurobiology and Consequences of Social Isolation Stress in Animal Model-A Comprehensive Review","volume":"105","author":"Mumtaz","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00429-016-1218-9","article-title":"Oxidative and Nitrosative Stress Pathways in the Brain of Socially Isolated Adult Male Rats Demonstrating Depressive- and Anxiety-like Symptoms","volume":"222","author":"Bernardi","year":"2017","journal-title":"Brain Struct. Funct."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11010-014-2045-z","article-title":"Different Susceptibility of Prefrontal Cortex and Hippocampus to Oxidative Stress Following Chronic Social Isolation Stress","volume":"393","author":"Demajo","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neuroscience.2022.08.011","article-title":"Chronic Fluoxetine Treatment of Socially Isolated Rats Modulates Prefrontal Cortex Proteome","volume":"501","author":"Novak","year":"2022","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0149-7634(05)80194-0","article-title":"Chronic Mild Stress-Induced Anhedonia: A Realistic Animal Model of Depression","volume":"16","author":"Willner","year":"1992","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.neubiorev.2005.03.008","article-title":"Assessing Substrates Underlying the Behavioral Effects of Antidepressants Using the Modified Rat Forced Swimming Test","volume":"29","author":"Cryan","year":"2005","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.neuropharm.2018.03.034","article-title":"Proteomic Characterization of Hippocampus of Chronically Socially Isolated Rats Treated with Fluoxetine: Depression-like Behaviour and Fluoxetine Mechanism of Action","volume":"135","author":"Costina","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00406-017-0807-9","article-title":"Fluoxetine Reverses Behavior Changes in Socially Isolated Rats: Role of the Hippocampal GSH-Dependent Defense System and Proinflammatory Cytokines","volume":"267","author":"Gass","year":"2017","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.brainres.2015.01.010","article-title":"Alterations in the Nrf2\u2013Keap1 Signaling Pathway and Its Downstream Target Genes in Rat Brain under Stress","volume":"1602","author":"Djordjevic","year":"2015","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.yhbeh.2012.03.001","article-title":"Testosterone and Imipramine Have Antidepressant Effects in Socially Isolated Male but Not Female Rats","volume":"61","author":"Carrier","year":"2012","journal-title":"Horm. Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ynstr.2014.11.002","article-title":"Resilience to the Effects of Social Stress: Evidence from Clinical and Preclinical Studies on the Role of Coping Strategies","volume":"1","author":"Wood","year":"2015","journal-title":"Neurobiol. Stress"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.cell.2007.09.018","article-title":"Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions","volume":"131","author":"Krishnan","year":"2007","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"M111.016428","DOI":"10.1074\/mcp.M111.016428","article-title":"Candidate Hippocampal Biomarkers of Susceptibility and Resilience to Stress in a Rat Model of Depression","volume":"11","author":"Henningsen","year":"2012","journal-title":"Mol. Cell. Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/jcpp.12054","article-title":"Annual Research Review: The Neurobiology and Physiology of Resilience and Adaptation across the Life Course","volume":"54","author":"Karatoreos","year":"2013","journal-title":"J. Child Psychol. Psychiatry Allied Discip."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/nn.3234","article-title":"Neurobiology of Resilience","volume":"15","author":"Russo","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.biopsych.2019.04.011","article-title":"Neurobiology of Resilience: Interface Between Mind and Body","volume":"86","author":"Cathomas","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Larosa, A., and Wong, T.P. (2022). The Hippocampus in Stress Susceptibility and Resilience: Reviewing Molecular and Functional Markers. Prog. Neuro Psychopharmacol. Biol. Psychiatry, 119.","DOI":"10.1016\/j.pnpbp.2022.110601"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1038\/nn.4086","article-title":"Mechanisms of Stress in the Brain","volume":"18","author":"McEwen","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.biopsych.2006.02.013","article-title":"A Neurotrophic Model for Stress-Related Mood Disorders","volume":"59","author":"Duman","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1176\/jnp.9.3.471","article-title":"Limbic-Cortical Dysregulation: A Proposed Model of Depression","volume":"9","author":"Mayberg","year":"1997","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.biopsych.2019.07.017","article-title":"Distorted Cognitive Processes in Major Depression: A Predictive Processing Perspective","volume":"87","author":"Kube","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Liu, H., Zhang, C., Ji, Y., and Yang, L. (2018). Biological and Psychological Perspectives of Resilience: Is It Possible to Improve Stress Resistance?. Front. Hum. Neurosci., 12.","DOI":"10.3389\/fnhum.2018.00326"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/hipo.20155","article-title":"Stress and Adult Neurogenesis","volume":"16","author":"Mirescu","year":"2006","journal-title":"Hippocampus"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41586-018-0262-4","article-title":"Hippocampal Neurogenesis Confers Stress Resilience by Inhibiting the Ventral Dentate Gyrus","volume":"559","author":"Anacker","year":"2018","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrn3229","article-title":"Impaired Mitochondrial Function in Psychiatric Disorders","volume":"13","author":"Manji","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/4151030a","article-title":"Functional Neurogenesis in the Adult Hippocampus","volume":"415","author":"Schinder","year":"2002","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.neubiorev.2013.02.005","article-title":"Mitochondria and the Economy of Stress (Mal)Adaptation","volume":"37","author":"Morava","year":"2013","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/PSY.0000000000000545","article-title":"Psychological Stress and Mitochondria: A Systematic Review","volume":"80","author":"Picard","year":"2018","journal-title":"Psychosom. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15486","DOI":"10.1073\/pnas.1512653112","article-title":"Mitochondrial Function in the Brain Links Anxiety with Social Subordination","volume":"112","author":"Hollis","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Allen, J., Romay-Tallon, R., Brymer, K.J., Caruncho, H.J., and Kalynchuk, L.E. (2018). Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00386"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Khan, M., Baussan, Y., and Hebert-Chatelain, E. (2023). Connecting Dots between Mitochondrial Dysfunction and Depression. Biomolecules, 13.","DOI":"10.3390\/biom13040695"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.biopsych.2017.09.010","article-title":"What Can Mitochondrial DNA Analysis Tell Us About Mood Disorders?","volume":"83","author":"Kasahara","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.yfrne.2018.01.001","article-title":"An Energetic View of Stress: Focus on Mitochondria","volume":"49","author":"Picard","year":"2018","journal-title":"Front. Neuroendocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"610","DOI":"10.2174\/1570159X14666160229114755","article-title":"Mitochondrial Dysfunction in Depression","volume":"14","author":"Bansal","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4847","DOI":"10.1007\/s12035-016-0032-y","article-title":"The Neurobiology of Depression: An Integrated Overview from Biological Theories to Clinical Evidence","volume":"54","author":"Ferrari","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zuccoli, G.S., Saia-Cereda, V.M., Nascimento, J.M., and Martins-de-Souza, D. (2017). The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00493"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s42255-022-00594-w","article-title":"Mitochondrial heterogeneity and homeostasis through the lens of a neuron","volume":"4","author":"Pekkurnaz","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.tcb.2017.01.005","article-title":"The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring","volume":"27","author":"Sheng","year":"2017","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s00018-023-04814-8","article-title":"Mitochondria as central hubs in synaptic modulation","volume":"80","author":"Duarte","year":"2023","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nrn.2017.170","article-title":"Mitochondria at the neuronal presynapse in health and disease","volume":"19","author":"Devine","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1021\/pr500295n","article-title":"Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial Vulnerability","volume":"13","author":"Stauch","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1046\/j.1471-4159.1996.66041617.x","article-title":"Threshold Effects and Control of Oxidative Phosphorylation in Nonsynaptic Rat Brain Mitochondria","volume":"66","author":"Davey","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5040","DOI":"10.1111\/ejn.16485","article-title":"Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions","volume":"60","author":"Ilaria","year":"2024","journal-title":"Eur. J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.neuint.2013.10.004","article-title":"Energy Metabolism of Cerebral Mitochondria during Aging, Ischemia and Post-Ischemic Recovery Assessed by Functional Proteomics of Enzymes","volume":"63","author":"Villa","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/BF00713032","article-title":"A Critique on the Preparation and Enzymatic Characterization of Synaptic and Nonsynaptic Mitochondria from Hippocampus","volume":"9","author":"Villa","year":"1989","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.neuroscience.2012.09.041","article-title":"Energy Metabolism of Rat Cerebral Cortex, Hypothalamus and Hypophysis during Ageing","volume":"227","author":"Villa","year":"2012","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"22325","DOI":"10.1074\/jbc.M115.656405","article-title":"The role of mitochondrially derived ATP in synaptic vesicle recycling","volume":"290","author":"Pathak","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"114218","DOI":"10.1016\/j.celrep.2024.114218","article-title":"Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses","volume":"43","author":"Myeong","year":"2024","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lopez-Manzaneda, M., Fuentes-Moliz, A., and Tabares, L. (2022). Presynaptic Mitochondria Communicate With Release Sites for Spatio-Temporal Regulation of Exocytosis at the Motor Nerve Terminal. Front. Synaptic Neurosci., 14.","DOI":"10.3389\/fnsyn.2022.858340"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.neuroscience.2016.05.051","article-title":"Effect of Desipramine and Fluoxetine on Energy Metabolism of Cerebral Mitochondria","volume":"330","author":"Villa","year":"2016","journal-title":"Neuroscience"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13024-017-0221-9","article-title":"Proteomic profiling of neuronal mitochondria reveals modulators of synaptic architecture","volume":"12","author":"Graham","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.neuron.2008.10.010","article-title":"Mitochondria in Neuroplasticity and Neurological Disorders","volume":"60","author":"Mattson","year":"2008","journal-title":"Neuron"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10254","DOI":"10.1016\/j.arr.2024.102524","article-title":"Synaptic Mitochondria: A Crucial Factor in the Aged Hippocampus","volume":"101","author":"Cicali","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.cell.2013.12.042","article-title":"Activity-Driven Local ATP Synthesis Is Required for Synaptic Function","volume":"156","author":"Rangaraju","year":"2014","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5411","DOI":"10.1242\/jcs.02745","article-title":"The axonal transport of mitochondria","volume":"118","author":"Hollenbeck","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.neuron.2012.08.019","article-title":"Synaptic energy use and supply","volume":"75","author":"Harris","year":"2012","journal-title":"Neuron"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1126\/science.1222939","article-title":"Synaptic dysfunction in depression: Potential therapeutic targets","volume":"338","author":"Duman","year":"2012","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/nm.2886","article-title":"Decreased expression of synapse-related genes and loss of synapses in major depressive disorder","volume":"18","author":"Kang","year":"2012","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"117790","DOI":"10.1016\/j.lfs.2020.117790","article-title":"Social Isolation Stress-Resilient Rats Reveal Energy Shift from Glycolysis to Oxidative Phosphorylation in Hippocampal Nonsynaptic Mitochondria","volume":"254","author":"Costina","year":"2020","journal-title":"Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.brainresbull.2020.11.013","article-title":"Hippocampal Synaptoproteomic Changes of Susceptibility and Resilience of Male Rats to Chronic Social Isolation","volume":"166","author":"Costina","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_68","first-page":"7.22.1","article-title":"Isolation of mitochondria from the CNS","volume":"7","author":"Kristian","year":"2010","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"105434","DOI":"10.1016\/j.neuint.2022.105434","article-title":"Social Isolation Induces Succinate Dehydrogenase Dysfunction in Anxious Mice","volume":"161","author":"Watanabe","year":"2022","journal-title":"Neurochem. Int."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Watanabe, S., Omran, A.A., Shao, A.S., Xue, C., Zhang, Z., Zhang, J., Davies, D.L., Shao, X.M., Watanabe, J., and Liang, J. (2022). Dihydromyricetin Improves Social Isolation-Induced Cognitive Impairments and Astrocytic Changes in Mice. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-09814-5"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"973","DOI":"10.2174\/1389450118666170816124203","article-title":"Mitochondrial Aconitase in Neurodegenerative Disorders: Role of a Metabolism- Related Molecule in Neurodegeneration","volume":"19","author":"Khodagholi","year":"2017","journal-title":"Curr. Drug Targets"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.tibs.2005.04.007","article-title":"Mitochondrial DNA, Aconitase \u201cwraps\u201d It Up","volume":"30","author":"Shadel","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41398-022-01856-7","article-title":"Metabolomic Signature and Mitochondrial Dynamics Outline the Difference between Vulnerability and Resilience to Chronic Stress","volume":"12","author":"Brivio","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0278-5846(01)00233-0","article-title":"ATPases Enzyme Activities during Ageing in Different Types of Somatic and Synaptic Plasma Membranes from Rat Frontal Cerebral Cortex","volume":"26","author":"Gorini","year":"2002","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12974-021-02368-9","article-title":"Social Isolation Induces Neuroinflammation and Microglia Overactivation, While Dihydromyricetin Prevents and Improves Them","volume":"19","author":"Shao","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cellsig.2010.08.003","article-title":"The Diverse Functions of GAPDH: Views from Different Subcellular Compartments","volume":"23","author":"Tristan","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"18947","DOI":"10.1074\/jbc.M113.466870","article-title":"Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Phosphorylation by Protein Kinase C\u03b4 (PKC\u03b4) Inhibits Mitochondria Elimination by Lysosomal-like Structures Following Ischemia and Reoxygenation-Induced Injury","volume":"288","author":"Yogalingam","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.cell.2007.03.045","article-title":"GAPDH and Autophagy Preserve Survival after Apoptotic Cytochrome c Release in the Absence of Caspase Activation","volume":"129","author":"Colell","year":"2007","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1042\/BST20130067","article-title":"GAPDH: The Missing Link between Glycolysis and Mitochondrial Oxidative Phosphorylation?","volume":"41","author":"Ramzan","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1083\/jcb.123.1.109","article-title":"A Dual Role for Mitochondrial Heat Shock Protein 70 in Membrane Translocation of Preproteins","volume":"123","author":"Gambill","year":"1993","journal-title":"J. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.tcb.2012.05.006","article-title":"Chaperone-Mediated Autophagy: A Unique Way to Enter the Lysosome World","volume":"22","author":"Kaushik","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"26374","DOI":"10.1016\/S0021-9258(18)47204-3","article-title":"Selective Binding and Uptake of Ribonuclease A and Glyceraldehyde-3-Phosphate Dehydrogenase by Isolated Rat Liver Lysosomes","volume":"269","author":"Cuervo","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/jnc.14471","article-title":"Mitochondria, Lysosomes, and Dysfunction: Their Meaning in Neurodegeneration","volume":"147","author":"Audano","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Willner, P. (2016). The Chronic Mild Stress (CMS) Model of Depression: History, Evaluation and Usage. Neurobiol. Stress, 6.","DOI":"10.1016\/j.ynstr.2016.08.002"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"175435","DOI":"10.1016\/j.ejphar.2022.175435","article-title":"Baicalin Ameliorates CUMS-Induced Depression-like Behaviors through Activating AMPK\/PGC-1\u03b1 Pathway and Enhancing NIX-Mediated Mitophagy in Mice","volume":"938","author":"Jin","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12305","DOI":"10.1074\/jbc.C200703200","article-title":"Mitochondrial ATP Synthasome: Cristae-Enriched Membranes and a Multiwell Detergent Screening Assay Yield Dispersed Single Complexes Containing the ATP Synthase and Carriers for Pi and ADP\/ATP","volume":"278","author":"Ko","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"9115","DOI":"10.1016\/S0021-9258(17)47273-5","article-title":"Mitochondrial Phosphate Transport. Large Scale Isolation and Characterization of the Phosphate Transport Protein from Beef Heart Mitochondria","volume":"259","author":"Kolbe","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.biopsych.2011.06.009","article-title":"Proteomics and Metabolomics Analysis of a Trait Anxiety Mouse Model Reveals Divergent Mitochondrial Pathways","volume":"70","author":"Filiou","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_90","first-page":"3561","article-title":"Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior","volume":"39","author":"Gokhale","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s00424-003-1099-7","article-title":"The Mitochondrial Transporter Family (SLC25): Physiological and Pathological Implications","volume":"447","author":"Palmieri","year":"2004","journal-title":"Pflugers Arch."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/dmr.5610050304","article-title":"Ketone Body Production and Disposal: Effects of Fasting, Diabetes, and Exercise","volume":"5","author":"Balasse","year":"1989","journal-title":"Diabetes. Metab. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/BST0340217","article-title":"Regulation of the Pyruvate Dehydrogenase Complex","volume":"34","author":"Patel","year":"2006","journal-title":"Biochem. Soc. Trans."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s12192-020-01080-6","article-title":"An Inventory of Interactors of the Human HSP60\/HSP10 Chaperonin in the Mitochondrial Matrix Space","volume":"25","author":"Bie","year":"2020","journal-title":"Cell Stress Chaperones"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1042\/BST0360976","article-title":"The Production of Reactive Oxygen Species by Complex I","volume":"36","author":"Hirst","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.bbabio.2012.12.002","article-title":"Superoxide Generation by Complex III: From Mechanistic Rationales to Functional Consequences","volume":"1827","author":"Bleier","year":"2013","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e15275","DOI":"10.7554\/eLife.15275","article-title":"Mitochondrial Support of Persistent Presynaptic Vesicle Mobilization with Age-Dependent Synaptic Growth after LTP","volume":"5","author":"Smith","year":"2016","journal-title":"Elife"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1038\/nprot.2008.171","article-title":"A Rapid Percoll Gradient Procedure for Preparation of Synaptosomes","volume":"3","author":"Dunkley","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1101\/pdb.top074450","article-title":"The Synaptosome as a Model System for Studying Synaptic Physiology","volume":"2015","author":"Evans","year":"2015","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3389\/fnsyn.2010.00139","article-title":"Synaptic Mitochondria in Synaptic Transmission and Organization of Vesicle Pools in Health and Disease","volume":"2","author":"Vos","year":"2010","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.neuron.2005.07.017","article-title":"Mitochondria and Neurotransmission: Evacuating the Synapse","volume":"47","author":"Hollenbeck","year":"2005","journal-title":"Neuron"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.mad.2008.01.006","article-title":"Changes in Dihydrolipoamide Dehydrogenase Expression and Activity during Postnatal Development and Aging in the Rat Brain","volume":"129","author":"Yan","year":"2008","journal-title":"Mech. Ageing Dev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/nrm2918","article-title":"HSP90 at the Hub of Protein Homeostasis: Emerging Mechanistic Insights","volume":"11","author":"Taipale","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.cell.2007.08.028","article-title":"Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network","volume":"131","author":"Kang","year":"2007","journal-title":"Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1007\/s00018-012-1177-0","article-title":"Hsp90 Regulation of Mitochondrial Protein Folding: From Organelle Integrity to Cellular Homeostasis","volume":"70","author":"Altieri","year":"2012","journal-title":"Cell. Mol. Life Sci. C"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5747","DOI":"10.1128\/MCB.02070-07","article-title":"The Chaperone-Mediated Autophagy Receptor Organizes in Dynamic Protein Complexes at the Lysosomal Membrane","volume":"28","author":"Bandyopadhyay","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.nbd.2018.05.010","article-title":"Chaperone-Mediated Autophagy: Advances from Bench to Bedside","volume":"122","author":"Li","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1111\/j.1742-4658.2009.06985.x","article-title":"Typical 2-Cys Peroxiredoxins-Structures, Mechanisms and Functions","volume":"276","author":"Hall","year":"2009","journal-title":"FEBS J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.freeradbiomed.2011.06.022","article-title":"Uncoupling Proteins and the Control of Mitochondrial Reactive Oxygen Species Production","volume":"51","author":"Mailloux","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrm.2017.20","article-title":"The HSP90 Chaperone Machinery","volume":"18","author":"Schopf","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Lackie, R.E., Maciejewski, A., Ostapchenko, V.G., Marques-Lopes, J., Choy, W.Y., Duennwald, M.L., Prado, V.F., and Prado, M.A.M. (2017). The Hsp70\/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00254"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e2403093","DOI":"10.1002\/advs.202403093","article-title":"CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore","volume":"11","author":"He","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"37361","DOI":"10.1074\/jbc.M604123200","article-title":"Mitochondrial Creatine Kinase Activity Prevents Reactive Oxygen Species Generation: Antioxidant Role of Mitochondrial Kinase-Dependent ADP Re-Cycling Activity","volume":"281","author":"Meyer","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.tem.2007.04.004","article-title":"Mitochondria as Key Components of the Stress Response","volume":"18","author":"Manoli","year":"2007","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1089\/ars.2017.7167","article-title":"The Role of Peroxiredoxins in the Transduction of H2O2 Signals","volume":"28","author":"Rhee","year":"2018","journal-title":"Antioxidants Redox Signal."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"108719","DOI":"10.1016\/j.neuropharm.2021.108719","article-title":"Glutamate Metabolism and Recycling at the Excitatory Synapse in Health and Neurodegeneration","volume":"196","author":"Andersen","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0197-0186(02)00033-5","article-title":"Glutamine Synthetase in Brain: Effect of Ammonia","volume":"41","author":"Bodega","year":"2002","journal-title":"Neurochem. Int."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neuropharm.2018.09.040","article-title":"Glutamine Has Antidepressive Effects through Increments of Glutamate and Glutamine Levels and Glutamatergic Activity in the Medial Prefrontal Cortex","volume":"143","author":"Son","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/s41401-024-01441-2","article-title":"Activation of Glutamine Synthetase (GS) as a New Strategy for the Treatment of Major Depressive Disorder and Other GS-Related Diseases","volume":"46","author":"Kang","year":"2025","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"15653","DOI":"10.1073\/pnas.0507901102","article-title":"Altered Cortical Glutamatergic and GABAergic Signal Transmission with Glial Involvement in Depression","volume":"102","author":"Choudary","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.tins.2019.07.002","article-title":"Anxiety and Brain Mitochondria: A Bidirectional Crosstalk","volume":"42","author":"Filiou","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/npp.2015.171","article-title":"Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex","volume":"41","author":"McEwen","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"van der Werff, S.J.A., van den Berg, S.M., Pannekoek, J.N., Elzinga, B.M., and van der Wee, N.J.A. (2013). Neuroimaging Resilience to Stress: A Review. Front. Behav. Neurosci., 7.","DOI":"10.3389\/fnbeh.2013.00039"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1358\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:49:07Z","timestamp":1760035747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1358"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":123,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["biom15101358"],"URL":"https:\/\/doi.org\/10.3390\/biom15101358","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]}}}