A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking

J Cell Sci. 2017 Oct 15;130(20):3467-3480. doi: 10.1242/jcs.203216. Epub 2017 Aug 24.

Abstract

The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition. Mechanistically, this disrupted motility results from aberrant degradation of Miro2, a mitochondrial GTPase that links mitochondria to microtubules. Rescue experiments demonstrate that this Miro2 degradation involves the KEAP1-cullin-3 E3 ubiquitin ligase and the proteasome. These data are consistent with a model in which an intact complex of PGAM5-KEAP1-Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. These data further provide a mechanistic explanation for how age-dependent declines in Nrf2 expression impact mitochondrial motility and induce functional deficits commonly linked to neurodegeneration.

Keywords: Clustering; Miro2; Mitochondria; Nrf2; Proteasome; Ubiquitin.

MeSH terms

  • Animals
  • Biological Transport
  • Female
  • HEK293 Cells
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Membrane Potential, Mitochondrial
  • Mice, Inbred C57BL
  • Microtubules / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics
  • Mitochondrial Proteins / metabolism*
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress*
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Domains
  • Proteolysis
  • rho GTP-Binding Proteins / metabolism

Substances

  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • PGAM5 protein, human
  • Phosphoprotein Phosphatases
  • RHOT2 protein, human
  • rho GTP-Binding Proteins