Vassilopoulos Athanassios, Pennington J Daniel, Andresson Thorkell, Rees David M, Bosley Allen D, Fearnley Ian M, Ham Amy, Flynn Charles Robb, Hill Salisha, Rose Kristie Lindsey, Kim Hyun-Seok, Deng Chu-Xia, Walker John E, Gius David
1 Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University , Chicago, Illinois.
Antioxid Redox Signal. 2014 Aug 1;21(4):551-64. doi: 10.1089/ars.2013.5420. Epub 2014 Mar 6.
Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis.
By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCP(K139) directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype.
This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins.
Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins.
三磷酸腺苷（ATP）合酶利用线粒体内膜两侧的化学渗透能将二磷酸腺苷和正磷酸盐转化为ATP，而Sirt3基因缺失会降低线粒体ATP水平。在此，我们研究SIRT3与能量稳态之间的机制联系。
通过体外和体内实验，我们证明ATP合酶F1蛋白α、β、γ和赋予寡霉素敏感性的蛋白（OSCP）含有SIRT3特异性的可逆乙酰赖氨酸，这些赖氨酸在进化上保守且与SIRT3结合。对OSCP进行了进一步研究，赖氨酸139是一个营养敏感的SIRT3依赖性去乙酰化靶点。定点突变表明，OSCP（K139）至少部分地指导线粒体ATP的产生，缺乏Sirt3的小鼠表现出ATP肌肉水平降低、ATP合酶蛋白乙酰化增加以及运动诱导的应激缺陷表型。
这项工作通过SIRT3对线粒体乙酰化组的指导，将衰老和营养反应与营养应激条件下线粒体能量稳态的调节联系起来，即通过使ATP合酶蛋白去乙酰化来实现。
我们的数据表明，乙酰化组信号通过SIRT3介导的ATP合酶蛋白去乙酰化作用，有助于线粒体能量稳态。
