Role of sirtuins on mitochondrial function and neurogenesis in different cellular models of hypoxia: relevance to the genesis and progression of schizophrenia.

Author(s)

Luiz Felipe Souza e Silva

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-11-04

Examining board members

Tatiana Rosado Rosenstock; Hudson de Sousa Buck; Carolina Demarchi Munhoz; Aline Camargo Ramos

• Advisor: Tatiana Rosado Rosenstock

Abstract

Hypoxia is an environmental factor correlated with complications in neurodevelopment because of mitochondrial dysfunction. Once sirtuins are involved in the regulation of mitochondrial and cellular metabolism we investigated whether sirtuins modulators could be a neuroprotective strategy against hypoxia. We used primary cortical astrocytes and neurons from of Wistar (control), and Spontaneous Hypertensive Rats (model of neonatal hypoxia and schizophrenia) exposed to the chemical hypoxia inducer, cobalt chloride (CoCl2). The cells were treated with CoCl2 (800 <font face = \"symbol\">mM and 2 mM) for 24 hours and were previously and simultaneously stimulated with Nicotinamide (50 <font face = \"symbol\">mM), Resveratrol (0.5 <font face = \"symbol\">mM) and Sirtinol (5 <font face = \"symbol\">mM) (48 hours). The mitochondrial calcium retention capacity, mitochondrial membrane potential and levels of reactive oxygen species were analyzed. In addition, genes related to mitochondrial metabolism, dynamics, and biogenesis, as well as levels of high-energy compounds were investigated. The chemical and neonatal hypoxia induced mitochondrial depolarization, decreased calcium retention capacity, and increased levels of ROS, Nfe2l2 expression and genes related to mitochondrial biogenesis and fission process. The hypoxia also decreased ATP levels and increased pyruvate and lactate levels. Prior exposure to all sirtuin modulators increased the viability of astrocytes and neurons, by increasing Nfe2l2 expression and decreasing ROS production. In astrocytes, there was still stimulation of mitochondrial biogenesis. While in neurons, there was an increase in the production of ATP, pyruvate, lactate, and an increase in the expression of genes related to mitochondrial fusion. Altogether, our results suggest that sirtuins modulators could be used as a protective strategy against hypoxia and contribute to a better understanding of their effects on the central nervous system and to a better understanding of mitochondrial function and its relationship to neurodevelopmental disorders. (AU)

• FAPESP's process: 18/13814-0 - The role of sirtuins on mitochondrial function and neurogenesis in different cellular models of hypoxia: relevance to schizophrenia genesis and progression
• Grantee: Luiz Felipe Souza e Silva
• Support Opportunities: Scholarships in Brazil - Doctorate