Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.
Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.
复制标题
心脏线粒体蛋白质组的极度乙酰化并不会引发心力衰竭。
DOI：
10.1161/circresaha.120.317293
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发表时间：
2020-09-25
影响因子：
20.1
通讯作者：
Muoio, Deborah M.
中科院分区：
文献类型：
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作者：
Davidson, Michael T.;Grimsrud, Paul A.;Lai, Ling;Draper, James A.;Fisher-Wellman, Kelsey H.;Narowski, Tara M.;Abraham, Dennis M.;Koves, Timothy R.;Kelly, Daniel P.;Muoio, Deborah M.
间接证据表明，心力衰竭的发生与线粒体蛋白的翻译后修饰有关，包括赖氨酸乙酰化(KAc)。尽管如此，KAC影响线粒体性能的直接证据仍然很少。这项研究试图探索线粒体KAc通过破坏氧化代谢而导致心力衰竭的前提。建立了肉碱乙酰转移酶(CrAT)和sirtuin 3(SIRT3)双基因敲除(DKO)小鼠系，分别通过缓冲乙酰基池和催化赖氨酸脱乙酰化来对抗KAc，建立了心肌线粒体KAc的定量乙酰蛋白质组学模型。由此产生的对线粒体生物能量学的影响使用呼吸诊断平台进行评估，该平台允许对线粒体功能和能量转导进行全面评估。采用经腹主动脉缩窄(TAC)作为心脏压力超负荷的模型，研究DKO小鼠对心力衰竭的易感性。DKO心脏的线粒体乙酰赖氨酸图谱的升高远远超过了压力超负荷或SIRT3缺乏的单独反应。在DKO和SIRT3KO心脏中测量的特定乙酰化赖氨酸肽丰度的相对变化具有很强的相关性。对多种高乙酰化设置的蛋白质组学比较显示，与实验性心力衰竭相比，受∼操作影响的KAc多肽群体之间有86%的重叠。尽管与其他疾病相比，DKO小鼠心脏KAc的严重程度，但线粒体功能的深层表型显示出令人惊讶的正常生物能量学特征。因此，在评估的>；120线粒体能量通量中，包括底物特异性脱氢酶活性、呼吸反应、氧化还原电荷、线粒体膜电位和电子泄漏，我们发现氧化不足的证据很少。同样，DKO心脏并不更容易受到TAC诱导的压力超负荷引起的功能障碍的影响。这些发现挑战了这样的前提，即超乙酰化本身通过导致线粒体氧化机制的广泛破坏而威胁到心肌的新陈代谢弹性。
Circumstantial evidence links the development of heart failure to post-translational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse. This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism. A dual knockout (DKO) mouse line with deficiencies in carnitine acetyltransferase (CrAT) and sirtuin 3 (Sirt3), enzymes that oppose Kac by buffering the acetyl group pool and catalyzing lysine deacetylation, respectively, was developed to model extreme mitochondrial Kac in cardiac muscle, as confirmed by quantitative acetyl-proteomics. The resulting impact on mitochondrial bioenergetics was evaluated using a respiratory diagnostics platform that permits comprehensive assessment of mitochondrial function and energy transduction. Susceptibility of DKO mice to heart failure was investigated using transaortic constriction (TAC) as a model of cardiac pressure overload. The mitochondrial acetyl-lysine landscape of DKO hearts was elevated well beyond that observed in response to pressure overload or Sirt3 deficiency alone. Relative changes in the abundance of specific acetylated lysine peptides measured in DKO versus Sirt3 KO hearts were strongly correlated. A proteomics comparison across multiple settings of hyperacetylation revealed ∼86% overlap between the populations of Kac peptides affected by the DKO manipulation as compared to experimental heart failure. Despite the severity of cardiac Kac in DKO mice relative to other conditions, deep phenotyping of mitochondrial function revealed a surprisingly normal bioenergetics profile. Thus, of the >120 mitochondrial energy fluxes evaluated, including substrate-specific dehydrogenase activities, respiratory responses, redox charge, mitochondrial membrane potential and electron leak, we found minimal evidence of oxidative insufficiencies. Similarly, DKO hearts were not more vulnerable to dysfunction caused by TAC-induced pressure overload. The findings challenge the premise that hyperacetylation per se threatens metabolic resilience in the myocardium by causing broad-ranging disruption to mitochondrial oxidative machinery.