Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5

J Biol Chem. 2012 Oct 5;287(41):34635-45. doi: 10.1074/jbc.M112.357509. Epub 2012 Aug 22.


Regulated intramembrane proteolysis is a widely conserved mechanism for controlling diverse biological processes. Considering that proteolysis is irreversible, it must be precisely regulated in a context-dependent manner. Here, we show that phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is cleaved in its N-terminal transmembrane domain in response to mitochondrial membrane potential (ΔΨ(m)) loss. This ΔΨ(m) loss-dependent cleavage of PGAM5 was mediated by presenilin-associated rhomboid-like (PARL). PARL is a mitochondrial resident rhomboid serine protease and has recently been reported to mediate the cleavage of PINK1, a mitochondrial Ser/Thr protein kinase, in healthy mitochondria with intact ΔΨ(m). Intriguingly, we found that PARL dissociated from PINK1 and reciprocally associated with PGAM5 in response to ΔΨ(m) loss. These results suggest that PARL mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria. Our data provide a prototypical example of stress-dependent regulation of PARL-mediated regulated intramembrane proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / physiology*
  • Metalloproteases / genetics
  • Metalloproteases / metabolism*
  • Mitochondrial Membranes / enzymology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Phosphoprotein Phosphatases
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proteolysis*


  • Carrier Proteins
  • Mitochondrial Proteins
  • Protein Kinases
  • PTEN-induced putative kinase
  • PGAM5 protein, human
  • Phosphoprotein Phosphatases
  • Metalloproteases
  • PARL protein, human