The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression
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...
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MDPI AG
2021-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/1/90 |
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| author | Sónia Sá Santos João B. Moreira Márcia Costa Rui S. Rodrigues Ana M. Sebastião Sara Xapelli Susana Solá |
| author_facet | Sónia Sá Santos João B. Moreira Márcia Costa Rui S. Rodrigues Ana M. Sebastião Sara Xapelli Susana Solá |
| author_sort | Sónia Sá Santos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:46:34Z |
| format | Article |
| id | doaj.art-9ac30f63c6a4477b80961fe424754494 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:46:34Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9ac30f63c6a4477b80961fe4247544942023-11-23T11:20:02ZengMDPI AGCells2073-44092021-12-011119010.3390/cells11010090The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and DepressionSónia Sá Santos0João B. Moreira1Márcia Costa2Rui S. Rodrigues3Ana M. Sebastião4Sara Xapelli5Susana Solá6Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalInstituto de Medicina Molecular (iMM) João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, PortugalInstituto de Medicina Molecular (iMM) João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, PortugalInstituto de Medicina Molecular (iMM) João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, PortugalNeural 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.https://www.mdpi.com/2073-4409/11/1/90agingdepressionlipid metabolismmitochondrianeural stem cellsSIRT3 |
| spellingShingle | Sónia Sá Santos João B. Moreira Márcia Costa Rui S. Rodrigues Ana M. Sebastião Sara Xapelli Susana Solá The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression Cells aging depression lipid metabolism mitochondria neural stem cells SIRT3 |
| title | The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression |
| title_full | The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression |
| title_fullStr | The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression |
| title_full_unstemmed | The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression |
| title_short | The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression |
| title_sort | mitochondrial antioxidant sirtuin3 cooperates with lipid metabolism to safeguard neurogenesis in aging and depression |
| topic | aging depression lipid metabolism mitochondria neural stem cells SIRT3 |
| url | https://www.mdpi.com/2073-4409/11/1/90 |
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