Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control

Abstract

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 CKO ) 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 S637 dephosphorylation but failed to abolish I/R-induce Drp1 S616 phosphorylation, resulting in partial inhibition of mitochondrial fission. In addition, declining Mfn2 and OPA1 levels were restored in PGAM5 CKO 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.

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…Phosphorylation of FUNDC1 at Ser13 hinders its binding to LC3-II Arg10 ( Lv et al, 2017 ). Phosphoglycerate mutase family member 5 (PGAM5) dephosphorylates FUNDC1 at Ser13 ( Zhu et al, 2021a ) thus enhancing the binding between FUNDC1 and LC3 ( Chen et al, 2014 ). However, creatine kinase 2 (CK2) can reverse PGAM5-induced FUNDC1 dephosphorylation and thus prevent mitophagy ( Chen et al, 2014 ).…”

“…Phosphoglycerate mutase family member 5-FUNDC1 may also have a synergistic effect on the PINK1/Parkin pathway. PINK1 was found to bind to PGAM5, and the absence of PGAM5 was reported to inhibit PINK1-induced mitophagy ( Park and Koh, 2020 ; Zhu et al, 2021a ). Moreover, knocking out FUNDC1 reduced Parkin translocation to the mitochondria ( Park and Koh, 2020 ).…”

RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK-Parkin-Mitophagy in Cardiac Remodelling after Myocardial Infarction

“…Numerous studies have shown that activation of mitophagy can inhibit mPTP opening [19][20][21]. The PINK1dependent recruitment of Parkin to damaged mitochondria is crucial in the process of mitophagy [22,23].…”

Tongyang Huoxue Decoction (TYHX) Ameliorating Hypoxia/Reoxygenation-Induced Disequilibrium of Calcium Homeostasis and Redox Imbalance via Regulating Mitochondrial Quality Control in Sinoatrial Node Cells

“…Mitochondrial quality control (MQC) is closely related to calcium homeostasis and redox balance [ 5 , 6 ], which directly affect the survival level of sinoatrial node cells (SANCs). Mitochondrion, as the central organelle of apoptosis pathway, is also the main site of tricarboxylic acid cycle and oxidative phosphorylation [ 7 ]. Its normal structure and function can meet the energy requirements of heart beating and ejection function, maintaining the homeostasis of intracellular environment, and regulating cell growth [ 8 , 9 ].…”