Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload
Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload
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DOI：
10.1074/jbc.ra118.002187
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发表时间：
2018-07-06
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.
线粒体Sirtuin 5（SIRT5）是一种NAD（+）依赖性脱丙二酸酶、脱琥珀酰酶和脱戊二酸酶，控制多种代谢途径。许多最近的研究指出SIRT5脱琥珀酸酶活性在维持应激下的心脏功能和代谢中是重要的。以前，我们描述了一个表型增加死亡率全身SIRT5KO小鼠暴露于慢性压力超负荷相比，其同窝野生型对照。为了确定我们报告的存活表型是否是由于SIRT5的心脏内在或心脏外在效应，我们开发了他莫昔芬诱导的心脏特异性SIRT5敲除（SIRT5KO）小鼠模型。使用我们的新动物模型，我们发现出生后Sirt5的心脏消融导致SIRT5耗尽后长达30周的蛋白琥珀酰化的持续积累。琥珀酰蛋白质组学显示，琥珀酰化增加的蛋白质的氧化代谢后15至31周。将心脏特异性SIRT5KO小鼠暴露于慢性压力超负荷以诱导心脏肥大。我们发现，与全身SIRT5KO小鼠相比，心脏特异性SIRT5KO小鼠及其同窝对照小鼠之间的存活率没有差异。总体而言，这里提供的数据表明，SIRT5KO小鼠的存活可能是由SIRT5的多组织或产前效应决定的。
Mitochondrial Sirtuin 5 (SIRT5) is an NAD(+)-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function and metabolism under stress. Previously, we described a phenotype of increased mortality in whole-body SIRT5KO mice exposed to chronic pressure overload compared with their littermate WT controls. To determine whether the survival phenotype we reported was due to a cardiac-intrinsic or cardiac-extrinsic effect of SIRT5, we developed a tamoxifen-inducible, heart-specific SIRT5 knockout (SIRT5KO) mouse model. Using our new animal model, we discovered that postnatal cardiac ablation of Sirt5 resulted in persistent accumulation of protein succinylation up to 30 weeks after SIRT5 depletion. Succinyl proteomics revealed that succinylation increased on proteins of oxidative metabolism between 15 and 31 weeks after ablation. Heart-specific SIRT5KO mice were exposed to chronic pressure overload to induce cardiac hypertrophy. We found that, in contrast to whole-body SIRT5KO mice, there was no difference in survival between heart-specific SIRT5KO mice and their littermate controls. Overall, the data presented here suggest that survival of SIRT5KO mice may be dictated by a multitissue or prenatal effect of SIRT5.