The membrane scaffold SLP2 anchors a proteolytic hub in mitochondria containing PARL and the i-AAA protease YME1L

EMBO Rep. 2016 Dec;17(12):1844-1856. doi: 10.15252/embr.201642698. Epub 2016 Oct 13.

Abstract

The SPFH (stomatin, prohibitin, flotillin, HflC/K) superfamily is composed of scaffold proteins that form ring-like structures and locally specify the protein-lipid composition in a variety of cellular membranes. Stomatin-like protein 2 (SLP2) is a member of this superfamily that localizes to the mitochondrial inner membrane (IM) where it acts as a membrane organizer. Here, we report that SLP2 anchors a large protease complex composed of the rhomboid protease PARL and the i-AAA protease YME1L, which we term the SPY complex (for SLP2-PARL-YME1L). Association with SLP2 in the SPY complex regulates PARL-mediated processing of PTEN-induced kinase PINK1 and the phosphatase PGAM5 in mitochondria. Moreover, SLP2 inhibits the stress-activated peptidase OMA1, which can bind to SLP2 and cleaves PGAM5 in depolarized mitochondria. SLP2 restricts OMA1-mediated processing of the dynamin-like GTPase OPA1 allowing stress-induced mitochondrial hyperfusion under starvation conditions. Together, our results reveal an important role of SLP2 membrane scaffolds for the spatial organization of IM proteases regulating mitochondrial dynamics, quality control, and cell survival.

Keywords: OMA1; SLP2; YME1L; membrane scaffold; mitochondria; rhomboid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Metalloproteases / genetics
  • Metalloproteases / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Peptide Hydrolases / metabolism
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Protein Binding
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proteolysis

Substances

  • Blood Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • STOML2 protein, human
  • Protein Kinases
  • PTEN-induced putative kinase
  • PGAM5 protein, human
  • Phosphoprotein Phosphatases
  • Metalloproteases
  • Peptide Hydrolases
  • PARL protein, human
  • Metalloendopeptidases
  • YME1L1 protein, human
  • molecule metalloprotease-related protein-1, human
  • GTP Phosphohydrolases
  • OPA1 protein, human
  • ATPases Associated with Diverse Cellular Activities