Mitochondrial SIRT3 confers neuroprotection in Huntington's disease by regulation of oxidative challenges and mitochondrial dynamics.

SIRT3 is a major regulator of mitochondrial acetylome. Here we show that SIRT3 is neuroprotective in Huntington's disease (HD), a motor neurodegenerative disorder caused by an abnormal expansion of polyglutamines in the huntingtin protein (HTT). Protein and enzymatic analysis revealed that increased SIRT3 is a signature in several HD models, including human HD brain, which is regulated by oxidative species. While loss of SIRT3 further aggravated the oxidative phenotype, antioxidant treatment regularized SIRT3 levels. SIRT3 overexpression promoted the antioxidant effect in cells expressing mutant HTT, leading to enhanced mitochondrial function and balanced dynamics. Decreased Fis1 and Drp1 accumulation in mitochondria induced by SIRT3 expression favored mitochondrial elongation, while the SIRT3 activator ε-viniferin improved anterograde mitochondrial neurite transport, sustaining cell survival. Notably, SIRT3 fly-ortholog dSirt2 overexpression in HD flies ameliorated neurodegeneration and extended lifespan. These findings provide a link between oxidative stress and mitochondrial dysfunction hypotheses in HD and offer an opportunity for therapeutic development.