Sirt3 Protects Cortical Neurons against Oxidative Stress via Regulating Mitochondrial Ca(2+) and Mitochondrial Biogenesis

Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD(+))-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate the role of Sirt3 in H(2)O(2) induced oxidative neuronal injury in primary cultured rat cortical neurons. We found that H(2)O(2) treatment significantly increased the expression of Sirt3 in a time-dependent manner at both mRNA and protein levels. Knockdown of Sirt3 with a specific small interfering RNA (siRNA) exacerbated H(2)O(2)-induced neuronal injury, whereas overexpression of Sirt3 by lentivirus transfection inhibited H(2)O(2)-induced neuronal damage reduced the generation of reactive oxygen species (ROS), and increased the activities of endogenous antioxidant enzymes. In addition, the intra-mitochondrial Ca(2+) overload, but not cytosolic Ca(2+) increase after H(2)O(2) treatment, was strongly attenuated after Sirt3 overexpression. Overexpression of Sirt3 also increased the content of mitochondrial DNA (mtDNA) and the expression of mitochondrial biogenesis related transcription factors. All these results suggest that Sirt3 acts as a prosurvival factor playing an essential role to protect cortical neurons under H(2)O(2) induced oxidative stress, possibly through regulating mitochondrial Ca(2+) homeostasis and mitochondrial biogenesis.