Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation
可逆琥珀酰化对棕色脂肪组织中UCP1和线粒体代谢的调节作用
摘要：
Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT-specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in global protein succinylation and malonylation. Mass spectrometry-based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl-mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.
棕色脂肪组织（BAT）富含线粒体，在能量消耗，产热和葡萄糖稳态中起重要作用。我们发现BAT中的线粒体蛋白质琥珀酰化和丙二酰化水平很高，并且受到生理和遗传调节。 BAT特异性缺失Sirt5，一种线粒体脱琥珀酰酶和去甲基化酶，导致全球蛋白质琥珀酰化和丙二酰化的显着增加。基于质谱的琥珀酰化定量分析表明，Sirt5调节BAT，UCP1中的关键产热蛋白。 UCP1中两种琥珀酰化赖氨酸突变为酰基模拟谷氨酰胺和谷氨酸显着降低其稳定性和活性。 UCP1和其他蛋白质在Sirt5KO BAT中的功能降低导致线粒体呼吸受损，线粒体自噬缺陷和代谢不灵活。因此，UCP1和其他线粒体蛋白的琥珀酰化在BAT和能量稳态的调节中起重要作用。
可逆琥珀酰化对棕色脂肪组织中UCP1和线粒体代谢的调节作用
摘要：
Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT-specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in global protein succinylation and malonylation. Mass spectrometry-based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl-mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.
棕色脂肪组织（BAT）富含线粒体，在能量消耗，产热和葡萄糖稳态中起重要作用。我们发现BAT中的线粒体蛋白质琥珀酰化和丙二酰化水平很高，并且受到生理和遗传调节。 BAT特异性缺失Sirt5，一种线粒体脱琥珀酰酶和去甲基化酶，导致全球蛋白质琥珀酰化和丙二酰化的显着增加。基于质谱的琥珀酰化定量分析表明，Sirt5调节BAT，UCP1中的关键产热蛋白。 UCP1中两种琥珀酰化赖氨酸突变为酰基模拟谷氨酰胺和谷氨酸显着降低其稳定性和活性。 UCP1和其他蛋白质在Sirt5KO BAT中的功能降低导致线粒体呼吸受损，线粒体自噬缺陷和代谢不灵活。因此，UCP1和其他线粒体蛋白的琥珀酰化在BAT和能量稳态的调节中起重要作用。
