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Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen\u2010based attentional set\u2010shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL\/6J mice. Volume electron microscopy of the mPFC revealed age\u2010related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria\u2010targeted antioxidant MitoQ improved attentional set\u2010shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.<\/jats:p>","DOI":"10.1111\/acel.70716","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:03:29Z","timestamp":1789373009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age\u2010Related Cognitive Inflexibility in Mice"],"prefix":"10.1111","volume":"25","author":[{"given":"Rui","family":"Yamada","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0983-8670","authenticated-orcid":false,"given":"Hirotaka","family":"Nagai","sequence":"additional","affiliation":[{"name":"Division of 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6536-2753","authenticated-orcid":false,"given":"Nobuhiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Division of Histology and Cell Biology, School of Medicine Jichi Medical University  Shimotsuke Japan"},{"name":"Division of Ultrastructural Research National Institute for Physiological Sciences  Okazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8089-8399","authenticated-orcid":false,"given":"Tomoyuki","family":"Furuyashiki","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Graduate School of Medicine Kobe University  Kobe Japan"},{"name":"Department of Pharmacology Graduate School of Medical and Dental Sciences, Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56342-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70041"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.48602"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-015-0176-7"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-11-04320.2000"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0839-11.2011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510303200"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1809"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.052373.115"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsz184"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142301.ns0207s59"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn2804"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.2741\/3303"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00019-2"},{"key":"e_1_2_10_16_1","article-title":"The 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H.Nagai Y.Zhu C.Numa M.Taniguchi andT.Furuyashiki.2026.\u201cAging Converts Microglial Repopulation Into Maladaptive Reprogramming That Exacerbates Cognitive Deficits.\u201dbioRxiv: the preprint server for biology.https:\/\/doi.org\/10.64898\/2026.01.08.698519.","DOI":"10.64898\/2026.01.08.698519"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2019.103409"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70716","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70716","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70716","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:06:34Z","timestamp":1790571994000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70716"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/acel.70716"],"URL":"https:\/\/doi.org\/10.1111\/acel.70716","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70716"}}