Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death.
Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death.
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DOI：
10.1161/circresaha.119.316306
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发表时间：
2020-01-17
影响因子：
20.1
通讯作者：
Murphy E
中科院分区：
文献类型：
--
作者：
Bauer TM;Murphy E
成人心肌细胞是有丝分裂后的细胞，细胞分裂非常有限。因此，心肌梗死期间发生的心肌细胞死亡对心脏有非常不利的后果。线粒体已成为心血管健康和疾病的重要调节因子。线粒体作为产生ATP的生物能量中心已经被证实，但也被证明可以调节细胞死亡途径。事实上，许多用于调节代谢和ATP产生的相同信号，如钙和活性氧，也是线粒体细胞死亡途径的关键调节因子。人们普遍假设，钙和活性氧的增加激活了线粒体内膜上一个被称为PTP（通透性过渡孔）的大电导通道，而这个孔的打开导致坏死上塌，这是一种受调节的坏死细胞死亡形式。已经提出了通过抑制PTP或抑制激活PTP的线粒体钙或活性氧的增加来减少PTP开放的策略。抑制PTP的一个主要限制是缺乏关于形成PTP的蛋白质的身份以及它们如何被钙和活性氧激活的知识。这篇综述将批判性地评估PTP成孔单元的候选物，并讨论最近的数据，这些数据表明PTP是由单一分子身份形成的假设可能需要重新考虑。
Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.