Mitochondrial Bioenergetics and Dysfunction in Failing Heart
Mitochondrial Bioenergetics and Dysfunction in Failing Heart
复制标题
DOI：
10.1007/978-3-319-55330-6_4
复制
发表时间：
2017-01-01
期刊：
影响因子：
--
通讯作者：
Pepe, Salvatore
中科院分区：
文献类型：
--
作者：
Sheeran, Freya L.;Pepe, Salvatore
能量不足已被认为是收缩期心力衰竭的一个关键特征。虽然线粒体长期以来一直被认为维持心肌能量供应，但治疗线粒体生物能量功能障碍的能力受到多种干扰的复杂相互作用的阻碍，这些干扰逐渐复合导致心肌衰竭和衰竭。与未衰竭的人类供者心脏相比，终末期心力衰竭患者的复合体I和IV、烟酰胺核苷酸转氢酶（nadph -转氢酶，Nnt）和Krebs循环酶异柠檬酸脱氢酶、苹果酸脱氢酶和乌头酸酶的活性明显降低。氧化还原能力降低，总谷胱甘肽和辅酶q10水平降低也是慢性左心室衰竭的特征。酶活性的降低部分与大量和高度特异性的氧化、亚硝基化和超乙酰化修饰有关。在这篇简短的综述中，我们强调了终末期衰竭的人左心室能量缺乏主要涉及关键电子传递链和克雷布斯循环酶的活性受损，而不是各自基因或蛋白质的表达改变。这些酶亚基结构的氧化修饰增强，以及高活性次级代谢物的形成，与线粒体活性氧管理能力下降导致的功能障碍有关，这进一步导致了人类心力衰竭中生物能量能力和收缩功能的逐渐下降。
Energy insufficiency has been recognized as a key feature of systolic heart failure. Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse. Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure. Diminished REDOX capacity with lower total glutathione and coenzyme Q10levels are also a feature of chronic left ventricular failure. Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications. In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins. Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure.