Roles of mitochondrial sirtuins in mitochondrial function, redox homeostasis, insulin resistance and type 2 diabetes.

Mitochondria are the metabolic hubs that process a number of reactions including tricarboxylic acid cycle, β-oxidation of fatty acids and part of the urea cycle and pyrimidine nucleotide biosynthesis. Mitochondrial dysfunction impairs redox homeostasis and metabolic adaptation, leading to aging and metabolic disorders like insulin resistance and type 2 diabetes. SIRT3, SIRT4 and SIRT5 belong to the sirtuin family proteins and are located at mitochondria and also known as mitochondrial sirtuins. They catalyze NAD+-dependent deacylation (deacetylation, demalonylation and desuccinylation) and ADP-ribosylation and modulate the function of mitochondrial targets to regulate the metabolic status in mammalian cells. Emerging evidence has revealed that mitochondrial sirtuins coordinate the regulation of gene expression and activities of a wide spectrum of enzymes to orchestrate oxidative metabolism and stress responses. Mitochondrial sirtuins act in synergistic or antagonistic manners to promote respiratory function, antioxidant defense, insulin response and adipogenesis to protect individuals from aging and aging-related metabolic abnormalities. In this review, we focus on the molecular mechanisms by which mitochondrial sirtuins regulate oxidative metabolism and antioxidant defense and discuss the roles of their deficiency in the impairment of mitochondrial function and pathogenesis of insulin resistance and type 2 diabetes.2

线粒体（mitochondria）作为代谢枢纽，参与催化包括三羧酸循环（tricarboxylic acid cycle）、脂肪酸β氧化、部分尿素循环（urea cycle）以及嘧啶核苷酸生物合成（pyrimidine nucleotide biosynthesis）在内的多种生化反应。线粒体功能障碍会破坏氧化还原稳态（redox homeostasis）与代谢适应性（metabolic adaptation），进而引发衰老以及胰岛素抵抗、2型糖尿病等代谢紊乱。SIRT3、SIRT4和SIRT5属于沉默信息调节因子家族蛋白（sirtuin family proteins），定位于线粒体，又被称为线粒体sirtuins（mitochondrial sirtuins）。它们催化依赖于烟酰胺腺嘌呤二核苷酸（NAD+）的脱酰基反应（包括去乙酰化、去丙二酰化和去琥珀酰化）以及二磷酸腺苷核糖基化（ADP-ribosylation）反应，并通过调控线粒体靶蛋白的功能，调节哺乳动物细胞（mammalian cells）内的代谢状态。日益增多的研究证据表明，线粒体sirtuins可协同调控基因表达与多种酶的活性，从而统筹调控氧化代谢与应激反应。线粒体sirtuins以协同或拮抗的方式发挥作用，促进呼吸功能、抗氧化防御、胰岛素应答与脂肪生成，帮助机体抵御衰老及衰老相关的代谢异常。在本综述中，我们将聚焦线粒体sirtuins调控氧化代谢与抗氧化防御的分子机制，并探讨其表达缺失在线粒体功能损伤以及胰岛素抵抗、2型糖尿病的发病机制中所发挥的作用。