Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice
Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice
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DOI：
10.1126/science.aad0116
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发表时间：
2015-12-04
期刊：
影响因子：
56.9
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Wai, Timothy;Garcia-Prieto, Jaime;Langer, Thomas
线粒体形态是由其膜的融合和分裂形成的。在这里，我们发现成人心肌功能取决于平衡的线粒体融合和裂变，通过线粒体肽酶 YME1L 和 OMA1 处理动力样鸟苷三磷酸酶 OPA1 来维持。小鼠体内 Yme1l 的心脏特异性消融会激活 OMA1 并加速 OPA1 蛋白水解，从而引发线粒体断裂并改变心脏代谢。这导致扩张型心肌病和心力衰竭。 Oma1 缺失可阻止 OPA1 裂解，从而挽救了心脏功能和线粒体形态。给小鼠喂食高脂肪饮食或消除骨骼肌中的 Yme1l 可以恢复心脏代谢并保留心脏功能，而不会抑制线粒体断裂。因此，未加工的 OPA1 足以维持心脏功能，OMA1 是心肌细胞存活的关键调节因子，线粒体形态与心脏代谢密切相关。
Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.