Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation

Cell Metab. 2013 Dec 3;18(6):908-19. doi: 10.1016/j.cmet.2013.11.006.

Abstract

Stress-regulated signaling pathways protect mitochondrial proteostasis and function from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. We identify Tim17A as a stress-regulated subunit of the translocase of the inner membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eukaryotic initiation factor 2α (eIF2α) phosphorylation through a mechanism dependent on the mitochondrial protease YME1L. Furthermore, we demonstrate that decreasing Tim17A attenuates TIM23-dependent protein import, promotes the induction of mitochondrial unfolded protein response (UPR)-associated proteostasis genes, and confers stress resistance in C. elegans and mammalian cells. Thus, our results indicate that Tim17A degradation is a stress-responsive mechanism by which cells adapt mitochondrial protein import efficiency and promote mitochondrial proteostasis in response to the numerous pathologic insults that induce stress-regulated translation attenuation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • Arsenic / toxicity
  • Caenorhabditis elegans / metabolism
  • Cell Line
  • Eukaryotic Initiation Factor-2 / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Metalloendopeptidases / antagonists & inhibitors
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins
  • Oxidative Stress* / drug effects
  • Paraquat / toxicity
  • Phosphorylation
  • Protein Biosynthesis / drug effects
  • Protein Transport / drug effects
  • Unfolded Protein Response / drug effects

Substances

  • Eukaryotic Initiation Factor-2
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • TIMM23 protein, human
  • Tim17 protein, human
  • Metalloendopeptidases
  • YME1L1 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • Arsenic
  • Paraquat