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