engleski

Loss of Sirtuin3 has an adverse male-specific efect on mitochondrial fitness and survival of mouse embryonic fibriblasts

Sexual dimorphism in metabolism has been observed in many animal species during early development. However, little is known about the molecular mechanisms underlying these differences. Sirtuin 3 (Sirt3) is the major mitochondrial deacetylase that plays an important role in regulating metabolic processes, but there is little information on its role in the context of sex differences in metabolic regulation. To test our hypothesis that the role of Sirt3 in metabolic regulation is sex-dependent in vitro, we measured proliferative, metabolic, antioxidant, and mitochondrial parameters in Sirt3 wild-type (WT) and knockout (KO) mouse embryonic fibroblasts (MEFs). We observed that depletion of Sirt3 results in reduced proliferation in both sexes, which is exacerbated in male MEFs. This suggests that Sirt3 is essential for cell viability, especially in male MEFs. Furthermore, we have shown that Sirt3 is upregulated in female MEFs, consistent with their higher energy status. In general, female MEFs had higher ATP production and more mitochondria than male MEFs in both genotypes. Loss of Sirt3 decreased mitochondrial membrane potential as well as CI- driven respiration coupled to ATP production in both sexes. Furthermore, we observed increased phosphorylation, i.e. activation of AMPK in Sirt3- depleted MEFs, and decreased levels of FASN and Scd-1, proteins involved in the anabolic process of de novo lipogenesis (DNL), whereas the levels of enzymes involved in fatty acid oxidation (HADHB) were increased. Overall, these results suggest that loss of Sirt3 results in lower energy levels in both sexes, with greater effects on male MEFs, contributing to their lower survival. In this study, we report for the first time unique sexspecific consequences of Sirt3 depletion and sex-specific patterns of mitochondrial function, energy status, and metabolic parameters in MEFs.

sirtuin 3, Sirt3, MEF

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