Sirtuins Modulators Counteract Mitochondrial Dysfunction in Cellular Models of Hypoxia: Relevance to Schizophrenia

• Published in: Neuroscience Vol. 524; pp. 269 - 284
• Main Authors: e Silva, Luiz Felipe Souza, Siena, Amanda, Yuzawa, Jessica Mayumi, Torresi, Jorge Luiz de Barros, Ziroldo, Alan, Rosenstock, Tatiana Rosado
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.08.2023
• Subjects: hypoxia; mitochondrial dysfunction; schizophrenia and astrocytes; sirtuins; hypoxia; mitochondrial dysfunction; schizophrenia and astrocytes; SHR; sirtuins; SZ
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2023.04.027

•Chemical and neonatal hypoxia causes mitochondrial dysfunction in astrocytes.•Astrocytes submitted to neonatal hypoxia have more mitochondria.•Sirts modulators restore mitochondrial function trough epigenetic modulation.•Sirts modulators protects astrocytes from induced chemical hypoxia cell death.•Sirts modulators increase key metabolic genes transcription and mitochondrial content in non-canonical way in astrocytes. Schizophrenia (SZ) is a neurodevelopmental-associated disorder strongly related to environmental factors, such as hypoxia. Because there is no cure for SZ or any pharmacological approach that could revert hypoxia-induced cellular damages, we evaluated whether modulators of sirtuins could abrogate hypoxia-induced mitochondrial deregulation as a neuroprotective strategy. Firstly, astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR), a model of both SZ and neonatal hypoxia, were submitted to chemical hypoxia. Then, cells were exposed to different concentrations of Nicotinamide (NAM), Resveratrol (Resv), and Sirtinol (Sir) for 48hrs. Our data indicate that sirtuins modulation reduces cell death increasing the acetylation of histone 3. This outcome is related to the rescue of loss of mitochondrial membrane potential, changes in mitochondrial calcium buffering capacity, decreased O2−rad levels and increased expression of metabolic regulators (Nrf-1 and Nfe2l2) and mitochondrial content. Such findings are relevant not only for hypoxia-associated conditions, named pre-eclampsia but also for SZ since prenatal hypoxia is a relevant environmental factor related to this burdensome neuropsychiatric disorder.