title: Transient and constitutive repression of cytoplasmic translation signaling in cells with mtDNA mutation.
abstract: Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA mutation or in mtDNA-less rho(0) cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor eIF-2alpha constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2 becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant cells. Independent of AMPK and mTOR, eIF-2alpha is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive protein synthesis inhibition through eIF-2alpha-mediated repression of translation initiation may have pathobiochemical consequences.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, The Netherlands. G.M.C.Janssen@lumc.nl
authors.forename: G M C
authors.initials: GM
authors.lastname: Janssen
authors.forename: P
authors.initials: P
authors.lastname: Schwertman
authors.forename: T A T
authors.initials: TA
authors.lastname: Wanga
authors.forename: R S Jahangir
authors.initials: RS
authors.lastname: Tafrechi
authors.forename: P J A
authors.initials: PJ
authors.lastname: van den Broek
authors.forename: A K
authors.initials: AK
authors.lastname: Raap
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D009154:Mutation; D010085:Oxidative Phosphorylation; D014176:Protein Biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D014475:Uncoupling Agents / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D014475:Uncoupling Agents; D055372:AMP-Activated Protein Kinases