Abstract
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.
Highlights
Diabetes present high level of glucose in the blood circulation and systemic metabolic abnormalities
These results indicate the importance of SIRT3 in redox homeostasis, especially to combat the oxidative stress induced by the high glucose/lipid environment of diabetic tissues [35]
Overexpression of SIRT3 mitigates excess lipids-induced ER stress and cell toxicity in β cells [52]. All these findings indicate the potential role of SIRT3 in the function of β cells and its protective effect against high glucose/lipids/reactive oxygen species (ROS) environment of insulin resistance and type 2 diabetes
Summary
Diabetes present high level of glucose in the blood circulation and systemic metabolic abnormalities. In this review, we focus on the mechanisms underlying SIRT3, SIRT4 and SIRT5-mediated regulation of mitochondrial function and metabolism (Figure 1), and discuss the implication of their deficiency in the pathogenesis of insulin resistance and type 2 diabetes. The expression of SIRT3 is reduced in the primary culture of skin fibroblasts of patients with large-scale mtDNA deletion or chronic progressive external ophthalmoplegia (CPEO) syndrome Oxidative stress from these pathogenic mtDNA mutations decreases SIRT3 expression, leading to a decline of respiratory enzyme function via post-translational modification [21]. H+/Ca2+ and Na+/Ca2+ exchangers (NCX) efflux Ca2+ ions from the matrix to the cytosol Tight regulation of these proteins is important to increase the Ca2+ level to activate mitochondrial enzymes and to prevent accumulation of Ca2+ ions and Ca2+ overload within the mitochondria [27]. As above-mentioned, the role of SIRT3 in regulating mPTP opening may contribute to the modulation of mitochondrial Ca2+ homeostasis
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