SIRT 3 , a modifier of mitochondrial function in Huntington's disease

SIRT 3 is the major regulator of the mitochondrial acetylome, mediating adaptive responses of neurons to metabolic challenges. Here, we speculated that targeting SIRT 3 might influence mitochondrial function and oxidative status that are abnormal in models of Huntingtonu0027s disease (HD), a motor neurodegenerative disorder mainly affecting the striatum. Protein and enzymatic analysis revealed that SIRT 3 is increased in several HD models. However, SIRT 3 knockdown aggravated mitochondrial-driven H 2 O 2 production and ATP levels. SIRT 3 levels in HD cells were normalized after antioxidant treatment, suggesting that augmented SIRT 3 may be triggered by oxidative stress. SIRT 3 overexpression (SIRT 3 OE) in HD striatal cells reestablished mitochondrial biogenesis markers, and functional imaging revealed improved mitochondrial membrane potential. Remarkably, the unbalanced mitochondrial dynamics observed in HD cells was reduced after SIRT 3 OE, with higher prevalence of tubular mitochondria due to decreased Drp1 accumulation. Additionally, overexpression of the Drosophila SIRT 3 ortholog dSirt 2 in HD model fruit flies reduced neurodegeneration of photoreceptor neurons. Overall, enhanced SIRT 3 activity ameliorates mitochondrial phenotypes, culminating in decreased neuronal damage in HD models.