{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T22:00:44Z","timestamp":1775944844008,"version":"3.50.1"},"reference-count":74,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-NEU\/29650\/2017"],"award-info":[{"award-number":["PTDC\/MED-NEU\/29650\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Neural stem cells (NSCs), crucial for memory in the adult brain, are also pivotal to buffer depressive behavior. However, the mechanisms underlying the boost in NSC activity throughout life are still largely undiscovered. Here, we aimed to explore the role of deacetylase Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, in the fate of NSC under aging and depression-like contexts. We showed that chronic treatment with tert-butyl hydroperoxide induces NSC aging, markedly reducing SIRT3 protein. SIRT3 overexpression, in turn, restored mitochondrial oxidative stress and the differentiation potential of aged NSCs. Notably, SIRT3 was also shown to physically interact with the long chain acyl-CoA dehydrogenase (LCAD) in NSCs and to require its activation to prevent age-impaired neurogenesis. Finally, the SIRT3 regulatory network was investigated in vivo using the unpredictable chronic mild stress (uCMS) paradigm to mimic depressive-like behavior in mice. Interestingly, uCMS mice presented lower levels of neurogenesis and LCAD expression in the same neurogenic niches, being significantly rescued by physical exercise, a well-known upregulator of SIRT3 and lipid metabolism. Our results suggest that targeting NSC metabolism, namely through SIRT3, might be a suitable promising strategy to delay NSC aging and confer stress resilience.<\/jats:p>","DOI":"10.3390\/cells11010090","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"90","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression"],"prefix":"10.3390","volume":"11","author":[{"given":"S\u00f3nia S\u00e1","family":"Santos","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7736-844X","authenticated-orcid":false,"given":"Jo\u00e3o B.","family":"Moreira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular (iMM) Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"given":"M\u00e1rcia","family":"Costa","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9343-745X","authenticated-orcid":false,"given":"Rui S.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular (iMM) Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"},{"name":"Instituto de Farmacologia e Neuroci\u00eancias, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"given":"Ana M.","family":"Sebasti\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular (iMM) Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"},{"name":"Instituto de Farmacologia e Neuroci\u00eancias, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6854-2509","authenticated-orcid":false,"given":"Sara","family":"Xapelli","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular (iMM) Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"},{"name":"Instituto de Farmacologia e Neuroci\u00eancias, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2036-797X","authenticated-orcid":false,"given":"Susana","family":"Sol\u00e1","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.stem.2018.04.004","article-title":"Human Adult Neurogenesis: Evidence and Remaining Questions","volume":"23","author":"Kempermann","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/cr.2009.56","article-title":"Adult neural stem cells in the mammalian central nervous system","volume":"19","author":"Ma","year":"2009","journal-title":"Cell Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.brainres.2015.04.029","article-title":"Classic and novel stem cell niches in brain homeostasis and repair","volume":"1628 Pt B","author":"Lin","year":"2015","journal-title":"Brain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.stem.2015.09.003","article-title":"Adult mammalian neural stem cells and neurogenesis: Five decades later","volume":"17","author":"Bond","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nrn1867","article-title":"Adult neurogenesis and functional plasticity in neuronal circuits","volume":"7","author":"Lledo","year":"2006","journal-title":"Nat. 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