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Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis

Wei Lu1, Junhui Sun2, Jeong Seon Yoon3

  • 1Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

Plos One
|January 26, 2016
PubMed

Insights

Phosphoglycerate mutase family member 5 (PGAM5) protects against necroptosis by promoting PINK1-dependent mitophagy. Loss of PGAM5 exacerbates cell death and oxidative damage, revealing a new therapeutic target for diseases involving necroptosis.

Area of Science:

  • Cellular Biology
  • Molecular Mechanisms of Cell Death
  • Mitochondrial Dynamics

Background:

  • Necroptosis is a regulated form of cell death involving RIP kinases and MLKL.
  • Phosphoglycerate mutase family member 5 (PGAM5) was previously thought to promote necroptosis.
  • The role of PGAM5 in cell death pathways requires further investigation.

Purpose of the Study:

  • To investigate the role of PGAM5 in necroptosis.
  • To elucidate the mechanism by which PGAM5 influences cell death.
  • To identify potential therapeutic targets for diseases associated with necroptosis.

Main Methods:

  • Generation of pgam5-deficient mice.
  • In vitro and in vivo induction of necroptosis.
  • Ischemic reperfusion injury models (heart and brain).
  • Electron microscopy, biochemical assays, and confocal microscopy.

Main Results:

  • PGAM5 deficiency exacerbated necroptosis in response to various stimuli.
  • PGAM5 is essential for PINK1-dependent mitophagy.
  • Loss of PGAM5 leads to mitochondrial accumulation, increased reactive oxygen species (ROS), and worsened necroptosis.
  • PGAM5 acts independently of the RIP1/RIP3 complex to promote mitophagy.

Conclusions:

  • PGAM5 protects cells from necroptosis by promoting mitophagy, contrary to previous assumptions.
  • PGAM5-mediated mitophagy antagonizes necroptosis by preventing mitochondrial dysfunction and ROS overproduction.
  • Targeting PGAM5-mediated mitophagy could be a therapeutic strategy for conditions like stroke and myocardial infarction.

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