SIRT2 mediates NADH-induced increases in Nrf2, GCL, and glutathione by modulating Akt phosphorylation in PC12 cells.

SIRT2 plays important roles in multiple biological processes. It is unclear whether SIRT2 affects antioxidant capacity by modulating Nrf2, a key transcription factor for multiple antioxidant genes. By studying NADH-treated differentiated PC12 cells, we found that NADH induced a significant increase in the nuclear Nrf2, which was prevented by both SIRT2 siRNA and SIRT2 inhibitor, AGK2. SIRT2 siRNA also blocked the NADH-induced increases in glutamate cysteine ligase (GCL) and glutathione. Moreover, SIRT2 siRNA and AGK2 blocked NADH-induced Akt phosphorylation, and inhibition of Akt phosphorylation prevented NADH-induced increases in the nuclear Nrf2 and glutathione. Collectively, our study shows that SIRT2 regulates nuclear Nrf2 levels by modulating Akt phosphorylation, thus modulating the levels of GCL and total glutathione.