The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble.
The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble.
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DOI：
10.1161/circresaha.116.303554
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发表时间：
2015-01-02
影响因子：
20.1
通讯作者：
Kitsis RN
中科院分区：
文献类型：
--
作者：
Dorn GW 2nd;Kitsis RN
线粒体研究正在经历复兴，部分原因是认识到这些原始原生细菌的内共生后代似乎正在追求自己的生物议程。线粒体代谢不仅需要产生支持其真核宿主（us）的大部分生化能量，而且线粒体可以主动（通过凋亡和程序性坏死）或被动（通过活性氧毒性）驱动细胞功能障碍或死亡。细胞线粒体集体通过生物源性更新和线粒体吞噬剔除来自动调节其种群;线粒体裂变和融合是线粒体动力学的两个组成部分，人们越来越认识到它们在这些过程中发挥着核心作用。线粒体动力学在横纹肌细胞中是罕见的，因此线粒体分裂和融合因子的心脏特异性遗传操作已被证明可用于揭示线粒体动力学蛋白的非经典功能。在这里，我们回顾了新描述的功能，线粒体融合/分裂蛋白在心脏线粒体质量控制，细胞死亡，钙信号，心脏发育。提出了一种机制的概念范式，其中细胞死亡和选择性细胞器剔除不是不同的过程，而是一个统一的和综合的质量控制机制，发挥不同的作用时，调用到不同程度，这取决于病理生理背景的组件。这为心肌细胞中线粒体动力学和死亡因子的看似矛盾的表达提供了一个合理的解释，其中线粒体形态重塑通常不会发生，并且从细胞自杀中恢复的能力受到严重限制。
Mitochondrial research is experiencing a renaissance in part due to the recognition that these endosymbiotic descendants of primordial protobacteria appear to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us), but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, two components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing non-canonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending upon pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamism and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited.