{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:02:16Z","timestamp":1789470136373,"version":"build-2803163510"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal\u2013mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer\u2019s disease, mitochondrial dysfunction and amyloid-\u03b2\/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions\u2014including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium\u2013glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists\u2014have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whether these responses can be safely and effectively modulated in humans will be essential for establishing its therapeutic relevance in metabolic and neurodegenerative diseases.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1892506","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:02:34Z","timestamp":1789466554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies"],"prefix":"10.3389","volume":"19","author":[{"given":"Toshiki","family":"Otoda","sequence":"first","affiliation":[{"name":"Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine","place":["Itabashi-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine, Nihon University School of Medicine","place":["Itabashi-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadateru","family":"Takayama","sequence":"additional","affiliation":[{"name":"Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine","place":["Itabashi-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e73138","DOI":"10.7554\/eLife.73138","article-title":"Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK biobank and meta-analyses","volume":"11","author":"Antal","year":"2022","journal-title":"eLife"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1007\/s11011-026-01895-9","article-title":"Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence","volume":"41","author":"Asadi Anar","year":"2026","journal-title":"Metab. Brain Dis."},{"key":"ref5001","doi-asserted-by":"publisher","first-page":"e214618","DOI":"10.1212\/WNL.0000000000214618","article-title":"What are the roles of mitochondrial stress responses and mitohormesis in neurodegenerative disorders?","volume":"106","author":"Benarroch","year":"2026","journal-title":"Neurology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e13770","DOI":"10.1111\/acel.13770","article-title":"Mitochondrial stress and mitokines in aging","volume":"22","author":"Burtscher","year":"2023","journal-title":"Aging Cell"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1016\/j.cmet.2023.10.011","article-title":"Mitohormesis","volume":"35","author":"Cheng","year":"2023","journal-title":"Cell Metab."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.clinthera.2026.02.010","article-title":"Effect of glucagon-like-Peptide-1 receptor agonists (GLP-1 RA) on neuropsychiatric outcomes: a systematic review and meta-analysis","volume":"48","author":"Choudhury","year":"2026","journal-title":"Clin. Ther."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/s41586-019-1911-y","article-title":"GDF15 mediates the effects of metformin on body weight and energy balance","volume":"578","author":"Coll","year":"2020","journal-title":"Nature"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1016\/j.cmet.2021.08.002","article-title":"Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes","volume":"33","author":"Crewe","year":"2021","journal-title":"Cell Metab."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1016\/S0140-6736(26)00459-9","article-title":"Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials","volume":"407","author":"Cummings","year":"2026","journal-title":"Lancet"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41573-020-0072-x","article-title":"Brain energy rescue: An emerging therapeutic concept for neurodegenerative disorders of ageing","volume":"19","author":"Cunnane","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s40659-024-00494-1","article-title":"The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration","volume":"57","author":"Da","year":"2024","journal-title":"Biol. Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"E2501","DOI":"10.1073\/pnas.1321776111","article-title":"Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2","volume":"111","author":"De Haes","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3233\/JAD-160656","article-title":"Improved brain insulin\/IGF signaling and reduced neuroinflammation with T3D-959 in an experimental model of sporadic Alzheimer\u2019s disease","volume":"55","author":"de la Monte","year":"2016","journal-title":"J. Alzheimer's Dis"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.2337\/dc24-0860","article-title":"Diabetes, prediabetes, and brain aging: the role of healthy lifestyle","volume":"47","author":"Dove","year":"2024","journal-title":"Diabetes Care"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1073\/pnas.1015950108","article-title":"Exercise training increases size of hippocampus and improves memory","volume":"108","author":"Erickson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41586-020-2076-4","article-title":"A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol","volume":"579","author":"Fessler","year":"2020","journal-title":"Nature"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1016\/j.cub.2016.06.002","article-title":"The transcription factor ATF5 mediates a mammalian mitochondrial UPR","volume":"26","author":"Fiorese","year":"2016","journal-title":"Curr. Biol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"5640","DOI":"10.1038\/s44318-025-00549-3","article-title":"Mammalian mitohormesis: from mitochondrial stressors to organismal benefits","volume":"44","author":"Gunawan","year":"2025","journal-title":"EMBO J."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/s41586-020-2078-2","article-title":"Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway","volume":"579","author":"Guo","year":"2020","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"318","DOI":"10.3390\/cells15040318","article-title":"Decoding the endocrine code of skeletal muscle: Myokines, exerkines, and inter-organ crosstalk in metabolic health and disease","volume":"15","author":"Hah","year":"2026","journal-title":"Cells"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1038\/ijo.2008.116","article-title":"AMPK: a key regulator of energy balance in the single cell and the whole organism","volume":"32","author":"Hardie","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.cell.2014.10.029","article-title":"Integrative biology of exercise","volume":"159","author":"Hawley","year":"2014","journal-title":"Cell"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1001\/jamaneurol.2023.4929","article-title":"Risk factors for young-onset dementia in the UK biobank","volume":"81","author":"Hendriks","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"12017","DOI":"10.1073\/pnas.0705070104","article-title":"AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha","volume":"104","author":"J\u00e4ger","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1745201","DOI":"10.3389\/fcell.2026.1745201","article-title":"Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases","volume":"14","author":"Ji","year":"2026","journal-title":"Front. Cell Dev. Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"eaea4205","DOI":"10.1126\/scitranslmed.aea4205","article-title":"Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice","volume":"18","author":"Jiang","year":"2026","journal-title":"Sci. Transl. Med."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1242\/jeb.090738","article-title":"The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease","volume":"217","author":"Jovaisaite","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.cmet.2021.01.003","article-title":"Mitohormesis in hypothalamic POMC neurons mediates regular exercise-induced high-turnover metabolism","volume":"33","author":"Kang","year":"2021","journal-title":"Cell Metab."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"C641","DOI":"10.1152\/ajpcell.00222.2006","article-title":"Mitochondria and neuronal activity","volume":"292","author":"Kann","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"320","DOI":"10.3390\/biom10020320","article-title":"Regulation of Nrf2 by mitochondrial reactive oxygen species in physiology and pathology","volume":"10","author":"Kasai","year":"2020","journal-title":"Biomolecules."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.cmet.2022.03.005","article-title":"Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure","volume":"34","author":"Katsumura","year":"2022","journal-title":"Cell Metab."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nm.3014","article-title":"Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine","volume":"19","author":"Kim","year":"2013","journal-title":"Nat. Med."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1038\/s12276-024-01211-4","article-title":"Socialized mitochondria: Mitonuclear crosstalk in stress","volume":"56","author":"Kim","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"110796","DOI":"10.1016\/j.exger.2019.110796","article-title":"Mitochondrial uncoupling and longevity\u2014a role for mitokines?","volume":"130","author":"Klaus","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.cmet.2023.11.014","article-title":"Mitochondrial-derived vesicles in metabolism, disease, and aging","volume":"36","author":"K\u00f6nig","year":"2024","journal-title":"Cell Metab."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e70174","DOI":"10.1002\/edm2.70174","article-title":"Risk of dementia in patients with type 2 diabetes using SGLT2 inhibitors versus DPP-4 inhibitors: a systematic review and meta-analysis","volume":"9","author":"Kumari","year":"2026","journal-title":"Endocrinol. Diabetes Metab."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1002\/hep.22183","article-title":"The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity","volume":"47","author":"Li","year":"2008","journal-title":"Hepatology"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1780247","DOI":"10.3389\/fnagi.2026.1780247","article-title":"Molecular mechanisms underlying exercise-enhanced autophagy in improving neuroplasticity in Alzheimer\u2019s disease","volume":"18","author":"Li","year":"2026","journal-title":"Front. Aging Neurosci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1083\/jcb.201607005","article-title":"The lysosome as a command-and-control center for cellular metabolism","volume":"214","author":"Lim","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","article-title":"Dementia prevention, intervention, and care: 2024 report of the lancet standing commission","volume":"404","author":"Livingston","year":"2024","journal-title":"Lancet"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"L\u00f3pez-Ot\u00edn","year":"2023","journal-title":"Cell"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1126\/science.1104343","article-title":"Mitochondrial dysfunction and type 2 diabetes","volume":"307","author":"Lowell","year":"2005","journal-title":"Science"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of nrf2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"874","DOI":"10.3390\/ijms20040874","article-title":"Insulin resistance and oxidative stress in the brain: what's new?","volume":"20","author":"Maciejczyk","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.cmet.2019.01.018","article-title":"Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential","volume":"29","author":"Madeo","year":"2019","journal-title":"Cell Metab."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1038\/s41467-024-46344-2","article-title":"The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease","volume":"15","author":"Manuello","year":"2024","journal-title":"Nat. Commun."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.arr.2007.08.007","article-title":"Hormesis defined","volume":"7","author":"Mattson","year":"2008","journal-title":"Ageing Res. Rev."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/j.neuron.2017.01.022","article-title":"Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities","volume":"93","author":"Menzies","year":"2017","journal-title":"Neuron"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"5157645","DOI":"10.1155\/2018\/5157645","article-title":"Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health","volume":"2018","author":"Miller","year":"2018","journal-title":"J. Nutr. Metab."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa2100708","article-title":"Donanemab in early Alzheimer\u2019s disease","volume":"384","author":"Mintun","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"6785","DOI":"10.1007\/s12035-024-04468-y","article-title":"Exploring the mechanisms and therapeutic approaches of mitochondrial dysfunction in Alzheimer\u2019s disease: An educational literature review","volume":"62","author":"Moawad","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1016\/S0140-6736(15)60461-5","article-title":"A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial","volume":"385","author":"Ngandu","year":"2015","journal-title":"Lancet"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"e192827","DOI":"10.1172\/jci.insight.192827","article-title":"Palmitate impairs autophagic degradation via oxidative stress\/perilysosomal Ca2+ overload\/mTORC1 activation pathway in pancreatic beta cells","volume":"10","author":"Nguyen","year":"2025","journal-title":"JCI Insight"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.3390\/biomedicines13051053","article-title":"Lysosomal stress in cardiovascular diseases: therapeutic potential of cardiovascular drugs and future directions","volume":"13","author":"Otoda","year":"","journal-title":"Biomedicines"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3390\/diabetology6100111","article-title":"Redox balance, mitohormesis, and organ stress in type 2 diabetes mellitus: mechanistic insights and the therapeutic role of SGLT2 inhibitors","volume":"6","author":"Otoda","year":"","journal-title":"Diabetology"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s44417-025-00007-y","article-title":"Comparative effects of imeglimin and empagliflozin on the redox-inflammation-organ stress axis in type 2 diabetes: a randomized controlled trial","volume":"1","author":"Otoda","year":"","journal-title":"Discov. Endocrinol. Metab."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s13300-023-01488-0","article-title":"Albuminuria and serum tumor necrosis factor receptor levels in patients with type 2 diabetes on SGLT2 inhibitors: a prospective study","volume":"15","author":"Otoda","year":"2024","journal-title":"Diabetes Ther."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.3390\/brainsci11081036","article-title":"Association between visceral fat and brain structural changes or cognitive function","volume":"11","author":"Ozato","year":"2021","journal-title":"Brain Sci."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Pakos-Zebrucka","year":"2016","journal-title":"EMBO Rep."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"e105271","DOI":"10.1136\/bmjopen-2025-105271","article-title":"Comparative risk of the neurodegenerative outcomes between sodium-glucose co-transporter 2 (SGLT2) inhibitors and thiazolidinediones in type 2 diabetes: a multicentre cohort study using the Korean healthcare database (2014\u20132025)","volume":"16","author":"Park","year":"2026","journal-title":"BMJ Open"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.arr.2018.08.003","article-title":"Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence","volume":"47","author":"Park","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1504718","DOI":"10.3389\/fendo.2024.1504718","article-title":"Editorial: role of mitochondrial stress response in metabolic health","volume":"15","author":"Pereira","year":"2024","journal-title":"Front. Endocrinol."},{"key":"ref3001","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40035-024-00435-8","article-title":"Neurodegenerative disorders, metabolic icebergs, and mitohormesis","volume":"13","author":"Phillips","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"13835","DOI":"10.3390\/ijms241813835","article-title":"Mitochondrial-derived vesicles: the good, the bad, and the ugly","volume":"24","author":"Picca","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","article-title":"Mitophagy and quality control mechanisms in mitochondrial maintenance","volume":"28","author":"Pickles","year":"2018","journal-title":"Curr. Biol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"3215","DOI":"10.1007\/s11010-026-05542-w","article-title":"The central role of mitochondrial dysfunction in neurodegeneration: implications for therapy","volume":"481","author":"Raafat","year":"2026","journal-title":"Mol. Cell. Biochem."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1089\/ars.2010.3393","article-title":"Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H(2)O(2), and protein chaperones","volume":"15","author":"Rhee","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/nm.3624","article-title":"Unraveling the truth about antioxidants: Mitohormesis explains ROS-induced health benefits","volume":"20","author":"Ristow","year":"2014","journal-title":"Nat. Med."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"288","DOI":"10.2203\/dose-response.13-035.Ristow","article-title":"Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS)","volume":"12","author":"Ristow","year":"2014","journal-title":"Dose-Response"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"e386","DOI":"10.1002\/edm2.386","article-title":"Functional consequences of brain exposure to saturated fatty acids: from energy metabolism and insulin resistance to neuronal damage","volume":"6","author":"Sanchez-Alegria","year":"2023","journal-title":"Endocrinol. Diabetes Metab."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1152\/physrev.00025.2007","article-title":"Transcriptional paradigms in mammalian mitochondrial biogenesis and function","volume":"88","author":"Scarpulla","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nrm.2017.110","article-title":"The mitochondrial UPR: mechanisms, physiological functions and implications in ageing","volume":"19","author":"Shpilka","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nrneurol.2010.130","article-title":"How does diabetes accelerate Alzheimer disease pathology?","volume":"6","author":"Sims-Robinson","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s40200-025-01800-8","article-title":"The association of metabolic syndrome and its components with brain volumes and structural connections: a systematic review and meta-analysis of observational studies","volume":"24","author":"Soleymani","year":"2025","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.clnu.2022.03.017","article-title":"Sarcopenic obesity is associated with cognitive impairment in community-dwelling older adults: the Bunkyo health study","volume":"41","author":"Someya","year":"2022","journal-title":"Clin. Nutr."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3390\/biology13060394","article-title":"Harnessing mitochondrial stress for health and disease: opportunities and challenges","volume":"13","author":"Sun","year":"2024","journal-title":"Biology"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrm.2017.66","article-title":"Mitochondrial diseases: the contribution of organelle stress responses to pathology","volume":"19","author":"Suomalainen","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.3233\/JAD-170585","article-title":"Mitochondria and mitochondrial cascades in Alzheimer\u2019s disease","volume":"62","author":"Swerdlow","year":"2018","journal-title":"J. Alzheimer's Dis"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/nrendo.2011.138","article-title":"The role of mitochondria in insulin resistance and type 2 diabetes mellitus","volume":"8","author":"Szendroedi","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s40520-025-03222-1","article-title":"Association of sarcopenic obesity with cognitive dysfunction and dementia: a systematic review and meta-analysis","volume":"37","author":"Tang","year":"2025","journal-title":"Aging Clin. Exp. Res."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"e12507","DOI":"10.1002\/dad2.12507","article-title":"Body mass index, weight change in midlife, and dementia incidence: the Japan public health center-based prospective study","volume":"15","author":"Tashiro","year":"2023","journal-title":"Alzheimers Dement"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"148733","DOI":"10.1016\/j.brainres.2023.148733","article-title":"Brain transcriptomic, metabolic and mitohormesis properties associated with N-propargylglycine treatment: a prevention strategy against neurodegeneration","volume":"1826","author":"Teramayi","year":"2024","journal-title":"Brain Res."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.cbi.2006.04.013","article-title":"The lysosomal-mitochondrial axis theory of postmitotic aging and cell death","volume":"163","author":"Terman","year":"2006","journal-title":"Chem. Biol. Interact."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1038\/s41467-021-21984-w","article-title":"Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs","volume":"12","author":"Todkar","year":"2021","journal-title":"Nat. Commun."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1089\/ars.2017.7342","article-title":"Transcriptional regulation by Nrf2","volume":"29","author":"Tonelli","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref91","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.3233\/JAD-161088","article-title":"Oxidative stress, synaptic dysfunction, and Alzheimer\u2019s disease","volume":"57","author":"T\u00f6nnies","year":"2017","journal-title":"J. Alzheimer's Dis"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in early Alzheimer\u2019s disease","volume":"388","author":"van Dyck","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41422-025-01203-7","article-title":"Mitophagy in the pathogenesis and management of disease","volume":"36","author":"Wang","year":"2026","journal-title":"Cell Res."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"e2603069123","DOI":"10.1073\/pnas.2603069123","article-title":"VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival","volume":"123","author":"Wang","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1039\/c8fo02460j","article-title":"Lycopene ameliorates systemic inflammation-induced synaptic dysfunction via improving insulin resistance and mitochondrial dysfunction in the liver-brain axis","volume":"10","author":"Wang","year":"2019","journal-title":"Food Funct."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"e13882","DOI":"10.1111\/obr.13882","article-title":"Estimating global prevalence of mild cognitive impairment and dementia in elderly with overweight, obesity, and central obesity: a systematic review and meta-analysis","volume":"26","author":"Wei","year":"2025","journal-title":"Obes. Rev."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/nature14951","article-title":"Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol","volume":"524","author":"Wrobel","year":"2015","journal-title":"Nature"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"4838","DOI":"10.1038\/s41467-026-71630-6","article-title":"The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency","volume":"17","author":"Yang","year":"2026","journal-title":"Nat. Commun."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrm3028","article-title":"Mechanisms of mitophagy","volume":"12","author":"Youle","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1126\/science.1219855","article-title":"Mitochondrial fission, fusion, and stress","volume":"337","author":"Youle","year":"2012","journal-title":"Science"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"2833","DOI":"10.1007\/s11010-026-05568-0","article-title":"Semaglutide ameliorates neuroinflammation and cognitive impairment in APP\/PS1 mice","volume":"481","author":"Yuan","year":"2026","journal-title":"Mol. Cell. Biochem."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1177\/13872877251329439","article-title":"Semaglutide improves cognitive function and neuroinflammation in APP\/PS1 transgenic mice by activating AMPK and inhibiting TLR4\/NF-\u03baB pathway","volume":"105","author":"Zhai","year":"2025","journal-title":"J. Alzheimer's Dis"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"964075","DOI":"10.3389\/fcell.2022.964075","article-title":"Role of Abeta in Alzheimer's-related synaptic dysfunction","volume":"10","author":"Zhang","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"6023","DOI":"10.1111\/dom.15977","article-title":"Associations of metabolic syndrome with cognitive function and dementia risk: evidence from the UK biobank cohort","volume":"26","author":"Zuo","year":"2024","journal-title":"Diabetes Obes. Metab."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1892506\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:02:35Z","timestamp":1789466555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1892506\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":106,"alternative-id":["10.3389\/fnmol.2026.1892506"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2026.1892506","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"1892506"}}