SIRT3

SIRT3 is the major mitochondrial protein lysine deacetylase and regulates mitochondrial homeostasis by deacetylating proteins involved in energy metabolism, antioxidant defense, and redox adaptation^[1][2]. Mechanistically, SIRT3 limits mitochondrial oxidative damage through targets including SOD2, PRDX3, COX4I2, and ALDH2, thereby linking lysine acetylation to reactive oxygen species control, respiratory-chain function, and aldehyde detoxification^[3][4][5][6]. In disease models, SIRT3 deletion promotes endothelial dysfunction, vascular inflammation, vascular hypertrophy, and age-dependent hypertension, whereas SIRT3 overexpression reduces vascular oxidative stress and attenuates angiotensin II- and deoxycorticosterone acetate-salt-induced hypertension^[3]. In intestinal ischemia/reperfusion injury, SIRT3-mediated PRDX3 deacetylation reduces mitochondrial oxidative damage and apoptosis; in osteoarthritis models, SIRT3 deacetylates COX4I2 to maintain mitochondrial respiratory-chain homeostasis and protect cartilage integrity^[4][5]. Compared with related isoforms, SIRT3 differs experimentally because it localizes to mitochondria, whereas structurally similar SIRT1 and SIRT2 localize primarily to the nucleus and cytosol^[7]. For experimental applications, honokiol activates SIRT3 in osteoarthritis models, while mitochondria-targeted SIRT3 inhibitors increase MnSOD acetylation with limited effects on known SIRT1 and SIRT2 targets^[5][7].