title: Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation.
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.
authors: Department of Molecular & Experimental Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: T Kelly
authors: TK
authors: Rainbolt
authors: Neli
authors: N
authors: Atanassova
authors: Joseph C
authors: JC
authors: Genereux
authors: R Luke
authors: RL
authors: Wiseman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001151:Arsenic / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000378:metabolism; D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D015852:Eukaryotic Initiation Factor-2; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C534731:TIMM17A protein, human; C438387:TIMM23 protein, human; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D001151:Arsenic; D010269:Paraquat