Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury

Abstract

Phosphoglycerate mutase 5 (PGAM5) is a mitochondrial membrane protein that plays crucial roles in necroptosis and apoptosis. Though PGAM5 is known to be required for inducing intrinsic apoptosis through interacting with BCL2 associated X protein (Bax) and dynamin-related protein 1 (Drp1), the expression and role of PGAM5 in cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury(MIRI) has not been studied. The present study shows that PGAM5 expression decreased after MIRI in vivo, positively correlated with Bcl-xL expression, negatively correlated with Kelch-ECH associating protein 1 (Keap1) expression. Furthermore, PGAM5 expression also decreased in cardiomyocytes after hypoxia/reoxygenation (H/R) treatment in vitro. PGAM5 silence promoted cardiomyocyte apoptosis and inhibited Bcl-xL expression, but with no effect on Keap1 expression. Accordingly, Keap1 overexpression further inhibited Bcl-xL and PGAM5 expression. Additionally, PGAM5-Bcl-xL-Keap1 interaction was identified, suggesting that PGAM5 might participate in the degradation of Bcl-xL mediated by Keap1. In summary, PGAM5 controls cardiomyocyte apoptosis induced by MIRI through regulating Keap1-mediated Bcl-xL degradation, which may supply a novel molecular target for acute myocardial infarction (AMI) therapy. Graphical abstract ᅟ.

High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients

“…The role of PGAM5 in HCC chemoresistance has not been established; previous reports have suggested that PGAM5 may be involved in apoptosis by interacting with Bcl-xL 31 . Interestingly, silencing PGAM5 reduced expression of the anti-apoptotic protein Bcl-xL in 7402 and HepG2 cells by western blotting (Fig.…”

The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis

“…Furthermore, PGAM5 is also a binding protein of the antiapoptotic protein, BCL-XL [31]. A decrease in PGAM5 may lead to KEAP1-mediated BCL-XL degradation, which thereby promotes apoptosis [32]. In particular, considering the reduction of NFE2L2 or PGAM5 in aging and human degenerative disease states [32–35], this NFE2L2-KEAP1-PGAM5 ternary interaction may be an important mechanism in the development of human diseases.…”

Barth syndrome cellular models have dysregulated respiratory chain complex I and mitochondrial quality control due to abnormal cardiolipin

“…When we analyzed the top five proteins with significantly increased abundance, we identified PARL as a candidate for further study due to its role in regulating mitochondrial responses to stress, such as membrane depolarization and increased reactive oxygen species (22–24). Additionally, dysregulation of PARL substrates has been implicated in cardiomyopathy and cardiac development, further highlighting the potential role of PARL dysregulation in BTHS (25–27). Upon further investigation of the 127 terms significantly enriched for proteins with a FC > 1.20, we observed that 20 terms reference the mitochondrion or mitochondrial dynamics, including: metabolic pathways (p=3.1 × 10 −3 ), positive regulation of the apoptotic process (p=4.2 × 10 −3 ), and mitochondrial inner membrane (p=5.2 × 10 −3 ) (Table S2B).…”

“…When we analyzed the top five proteins with significantly increased abundance, we identified PARL as a candidate for further study due to its role in regulating mitochondrial responses to stress, such as membrane depolarization and increased reactive oxygen species (22)(23)(24). Additionally, dysregulation of PARL substrates has been implicated in cardiomyopathy and cardiac development, further highlighting the potential role of PARL dysregulation in BTHS (25)(26)(27). Upon further investigation of the 127 terms significantly enriched for proteins with a FC > 1.…”