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

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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.

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (Nos. 81202368, 31270802, 81401365); Nantong science and technology project (MS12015056); a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Chen Yang, Zihao Chen, Daliang Yan & Qingsheng You

  2. Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, 226001, China

    Xiaojuan Liu

  3. Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu, 226001, China

    Xiaojuan Liu

  4. Department of Infection Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Fangfang Yang

  5. Medical College, Nantong University, Nantong, Jiangsu, 226001, China

    Weixun Zhang

  6. Department of Vasculocardiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China

    Xiang Wu

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  1. Chen Yang
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Correspondence to Qingsheng You or Xiang Wu.

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Editor: Tetsuji Okamoto

Chen Yang, Xiaojuan Liu, Qingsheng You, and Xiang Wu contributed equally to this work.

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Yang, C., Liu, X., Yang, F. et al. Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury. In Vitro Cell.Dev.Biol.-Animal 53, 248–257 (2017). https://doi.org/10.1007/s11626-016-0105-2

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