Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua City 50046, Taiwan.
Int J Mol Sci. 2020 Jul 24;21(15):5266. doi: 10.3390/ijms21155266.
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.
线粒体是代谢中心，可处理包括三羧酸循环、脂肪酸β-氧化和部分尿素循环以及嘧啶核苷酸生物合成在内的多种反应。线粒体功能障碍会破坏氧化还原平衡和代谢适应，导致衰老和代谢紊乱，如胰岛素抵抗和 2 型糖尿病。SIRT3、SIRT4 和 SIRT5 属于 sirtuin 家族蛋白，位于线粒体中，也称为线粒体 sirtuins。它们催化 NAD 依赖性脱酰基（去乙酰化、脱戊二酰基和脱琥珀酰基）和 ADP-核糖基化，并调节线粒体靶标的功能，以调节哺乳动物细胞的代谢状态。新出现的证据表明，线粒体 sirtuins 协调基因表达的调控和广泛的酶活性，以协调氧化代谢和应激反应。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、胰岛素反应和脂肪生成，以保护个体免受衰老和与衰老相关的代谢异常的影响。在这篇综述中，我们重点讨论了线粒体 sirtuins 调节氧化代谢和抗氧化防御的分子机制，并讨论了它们缺乏在损害线粒体功能和胰岛素抵抗及 2 型糖尿病发病机制中的作用。
