Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Redox Biol. 2021 Jan;38:101777. doi: 10.1016/j.redox.2020.101777. Epub 2020 Nov 1.
The death of cardiomyocytes either through apoptosis or necroptosis is the pathological feature of cardiac ischemia-reperfusion (I/R) injury. Phosphoglycerate mutase 5 (PGAM5), a mitochondrially-localized serine/threonine-protein phosphatase, functions as a novel inducer of necroptosis. However, intense debate exists regarding the effect of PGAM5 on I/R-related cardiomyocyte death. Using cardiac-specific PGAM5 knockout (PGAM5) mice, we comprehensively investigated the precise contribution and molecular mechanism of PGAM5 in cardiomyocyte death. Our data showed that both PGAM5 transcription and expression were upregulated in reperfused myocardium. Genetic ablation of PGAM5 suppressed I/R-mediated necroptosis but failed to prevent apoptosis activation, a result that went along with improved heart function and decreased inflammation response. Regardless of PGAM5 status, mitophagy-related cell death was not apparent following I/R. Under physiological conditions, PGAM5 overexpression in primary cardiomyocytes was sufficient to induce cardiomyocyte necroptosis rather than apoptosis. At the sub-cellular levels, PGAM5 deficiency increased mitochondrial DNA copy number and transcript levels, normalized mitochondrial respiration, repressed mitochondrial ROS production, and prevented abnormal mPTP opening upon I/R. Molecular investigation demonstrated that PGAM5 deletion interrupted I/R-mediated Drp dephosphorylation but failed to abolish I/R-induce Drp1 phosphorylation, resulting in partial inhibition of mitochondrial fission. In addition, declining Mfn2 and OPA1 levels were restored in PGAM5 cardiomyocytes following I/R. Nevertheless, PGAM5 depletion did not rescue suppressed mitophagy upon I/R injury. In conclusion, our results provide an insight into the specific role and working mechanism of PGAM5 in driving cardiomyocyte necroptosis through imposing mitochondrial quality control in cardiac I/R injury.
心肌细胞的凋亡或坏死是心肌缺血再灌注（I/R）损伤的病理特征。磷酸甘油酸变位酶 5（PGAM5），一种定位于线粒体的丝氨酸/苏氨酸蛋白磷酸酶，作为坏死的新型诱导剂。然而，PGAM5 对 I/R 相关的心肌细胞死亡的影响存在激烈的争论。使用心脏特异性 PGAM5 敲除（PGAM5）小鼠，我们全面研究了 PGAM5 在心肌细胞死亡中的精确作用和分子机制。我们的数据表明，PGAM5 的转录和表达在再灌注心肌中均上调。PGAM5 的基因缺失抑制了 I/R 介导的坏死，但未能阻止凋亡的激活，结果伴随着心功能的改善和炎症反应的降低。无论 PGAM5 的状态如何，I/R 后都没有明显的线粒体自噬相关细胞死亡。在生理条件下，原代心肌细胞中 PGAM5 的过表达足以诱导心肌细胞坏死而不是凋亡。在亚细胞水平上，PGAM5 缺乏增加了线粒体 DNA 拷贝数和转录水平，使线粒体呼吸正常化，抑制了线粒体 ROS 的产生，并防止了 I/R 后异常 mPTP 的开放。分子研究表明，PGAM5 缺失中断了 I/R 介导的 Drp 去磷酸化，但未能消除 I/R 诱导的 Drp1 磷酸化，导致线粒体分裂的部分抑制。此外，PGAM5 心肌细胞中 I/R 后下降的 Mfn2 和 OPA1 水平得到恢复。然而，PGAM5 耗竭并不能挽救 I/R 损伤后受抑制的线粒体自噬。总之，我们的结果提供了关于 PGAM5 在心脏 I/R 损伤中通过施加线粒体质量控制驱动心肌细胞坏死的具体作用和工作机制的深入了解。
