Sirtuin 5 is required for mouse survival in response to cardiac pressure overload
Sirtuin 5 is required for mouse survival in response to cardiac pressure overload
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DOI：
10.1074/jbc.m117.809897
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发表时间：
2017-12-01
影响因子：
4.8
通讯作者：
Hirschey, Matthew D.
中科院分区：
文献类型：
--
作者：
Hershberger, Kathleen A.;Abraham, Dennis M.;Hirschey, Matthew D.
在线粒体中，sirtuin SIRT 5是一种NAD（+）依赖性蛋白脱酰酶，控制着几种代谢途径。虽然已经鉴定了广泛的SIRT 5靶点，但SIRT 5在生物体代谢稳态中的总体功能仍不清楚。鉴于SIRT 5在心脏中的表达最高，并且sirtuins通常是应激反应蛋白，我们使用了由横主动脉缩窄（TAC）引起的压力超负荷诱导的心肌肥大的既定模型来确定SIRT 5在心脏应激反应中的作用。值得注意的是，与野生型小鼠相比，SIRT 5 KO小鼠在TAC后的存活率降低，但在进行假对照手术时没有表现出死亡率。TAC死亡率的增加与病理性肥大的增加以及心脏功能和心室顺应性的关键异常有关。通过对野生型和SIRT 5 KO小鼠的心脏组织进行高分辨率的基于MS的代谢组学和蛋白质组学分析，我们发现SIRT 5 KO小鼠的几种生化异常加剧，包括脂肪酸氧化和葡萄糖氧化的明显减少以及线粒体NAD（+）/NADH的总体减少。总之，这些异常表明SIRT 5使参与细胞氧化代谢的蛋白质底物脱酰基，以维持线粒体能量产生。总体而言，此处呈现的功能和代谢结果表明SIRT 5 KO小鼠中响应于TAC的心脏功能障碍的加速发展，解释了心脏应激时死亡率增加。我们的研究结果揭示了SIRT 5在压力超负荷下维持心脏氧化代谢以确保生存的关键作用。
In mitochondria, the sirtuin SIRT5 is an NAD(+)-dependent protein deacylase that controls several metabolic pathways. Although a wide range of SIRT5 targets have been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses. Remarkably, SIRT5KO mice had reduced survival upon TAC compared with wild-type mice but exhibited no mortality when undergoing a sham control operation. The increased mortality with TAC was associated with increased pathological hypertrophy and with key abnormalities in both cardiac performance and ventricular compliance. By combining high-resolution MS-based metabolomic and proteomic analyses of cardiac tissues from wild-type and SIRT5KO mice, we found several biochemical abnormalities exacerbated in the SIRT5KO mice, including apparent decreases in fatty acid oxidation and glucose oxidation as well as an overall decrease in mitochondrial NAD(+)/NADH. Together, these abnormalities suggest that SIRT5 deacylates protein substrates involved in cellular oxidative metabolism to maintain mitochondrial energy production. Overall, the functional and metabolic results presented here suggest an accelerated development of cardiac dysfunction in SIRT5KO mice in response to TAC, explaining increased mortality upon cardiac stress. Our findings reveal a key role for SIRT5 in maintaining cardiac oxidative metabolism under pressure overload to ensure survival.