Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteins during mitophagy

Biochim Biophys Acta Mol Cell Res. 2021 Jun;1868(7):119045. doi: 10.1016/j.bbamcr.2021.119045. Epub 2021 Apr 17.


PGAM5 is a protein phosphatase located in the inner mitochondrial membrane through its transmembrane (TM) domain and is cleaved within the TM domain upon mitochondrial dysfunction. We found previously that cleaved PGAM5 is released from mitochondria, following proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy, a selective form of autophagy specific to mitochondria. Here, we examined the role of cleaved PGAM5 outside mitochondria. Deletion mutants that mimic cleaved PGAM5 existed not only in the cytosol but also in the nucleus, and a fraction of cleaved PGAM5 translocated to the nucleus during mitophagy induced by the uncoupler CCCP. We identified serine/arginine-related nuclear matrix protein of 160 kDa (SRm160)/SRRM1, which contains a highly phosphorylated domain rich in arginine/serine dipeptides, called the RS domain, as a nuclear protein that interacts with PGAM5. PGAM5 dephosphorylated SRm160, and incubation of lysates from WT cells, but not of those from PGAM5-deficient cells, induced dephosphorylation of SRm160 and another RS domain-containing protein SRSF1, one of the most characterized serine/arginine-rich (SR) proteins. Moreover, phosphorylation of these proteins and other SR proteins, which are commonly reactive toward the 1H4 monoclonal antibody that detects phosphorylated SR proteins, decreased during mitophagy, largely because of PGAM5 activity. These results suggest that PGAM5 regulates phosphorylation of these nuclear proteins during mitophagy. Because SRm160 and SR proteins play critical roles in mRNA metabolism, PGAM5 may coordinate cellular responses to mitochondrial stress at least in part through post-transcriptional and pre-translational events.

Keywords: Mitochondria; Mitophagy; PGAM5; Parkin; Protein phosphatase; SR proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Nuclear / metabolism
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitophagy / genetics*
  • Mitophagy / physiology
  • Nuclear Matrix-Associated Proteins / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • RNA-Binding Proteins / metabolism
  • Serine-Arginine Splicing Factors / metabolism*
  • Serine-Arginine Splicing Factors / physiology
  • Ubiquitin-Protein Ligases / metabolism


  • Antigens, Nuclear
  • Membrane Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Nuclear Matrix-Associated Proteins
  • RNA-Binding Proteins
  • SRRM1 protein, human
  • Serine-Arginine Splicing Factors
  • Ubiquitin-Protein Ligases
  • PGAM5 protein, human
  • Phosphoprotein Phosphatases