The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism

Cell Rep. 2017 Feb 7;18(6):1458-1472. doi: 10.1016/j.celrep.2017.01.029.

Abstract

Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson's disease. The mammalian mitochondrial rhomboid protease, PARL, has been proposed as a regulator of PINK1/PARKIN-mediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (β cleavage), which is required for efficient mitophagy. We demonstrate that β cleavage responds to mitochondrial stress, triggered by the depletion of mitochondrial ATP. Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates β cleavage. Through regulating β cleavage and the production of a less active enzyme, PACT, PDK2 negatively regulates PINK1/PARKIN-mediated mitophagy. Taken together, we propose that PDK2/PARL senses defects in mitochondrial bioenergetics, integrating mitochondrial metabolism to mitophagy and MQC in human health and disease.

Keywords: intramembrane proteolysis; metabolism; mitochondrial biogenesis; mitophagy; rhomboid protease.

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Energy Metabolism / physiology
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Metalloproteases / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Mitophagy / physiology
  • Protein Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Ubiquitin-Protein Ligases

Substances

  • Mitochondrial Proteins
  • PDK2 protein, human
  • Pdk2 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Serine-Threonine Kinases
  • Metalloproteases
  • PARL protein, human

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