RRC ID 46137
Author Rainbolt TK, Atanassova N, Genereux JC, Wiseman RL.
Title Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation.
Journal Cell Metab
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.
Volume 18(6)
Pages 908-19
Published 2013-12-3
DOI 10.1016/j.cmet.2013.11.006
PII S1550-4131(13)00455-5
PMID 24315374
PMC PMC3904643
MeSH 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
IF 21.567
Times Cited 72
WOS Category ENDOCRINOLOGY & METABOLISM CELL BIOLOGY
Resource
C.elegans tm4525