title: Role of oxygen consumption in hypoxia protection by translation factor depletion.
abstract: The reduction of protein synthesis has been associated with resistance to hypoxic cell death. Which components of the translation machinery control hypoxic sensitivity and the precise mechanism has not been systematically investigated, although a reduction in oxygen consumption has been widely assumed to be the mechanism. Using genetic reagents in Caenorhabditis elegans, we examined the effect on organismal survival after hypoxia of knockdown of 10 factors functioning at the three principal steps in translation. Reduction-of-function of all 10 translation factors significantly increased hypoxic survival to varying degrees, not fully accounted for by the level of translational suppression. Measurement of oxygen consumption showed that strong hypoxia resistance was possible without a significant decrease in oxygen consumption. Hypoxic sensitivity had no correlation with lifespan or reactive oxygen species sensitivity, two phenotypes associated with reduced translation. Resistance to tunicamycin, which produces misfolded protein toxicity, was the only phenotype that significantly correlated with hypoxic sensitivity. Translation factor knockdown was also hypoxia protective for mouse primary neurons. These data show that translation factor knockdown is hypoxia protective in both C. elegans and mouse neurons and that oxygen consumption does not necessarily determine survival; rather, mitigation of misfolded protein toxicity is more strongly associated with hypoxic protection.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Scott
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Sun
authors.forename: Xianrong
authors.initials: X
authors.lastname: Mao
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.forename: Bhupinder P S
authors.initials: BP
authors.lastname: Vohra
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: C Michael
authors.initials: CM
authors.lastname: Crowder
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000502:physiology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000502:physiology*; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D014162:Transfection; D014415:Tunicamycin / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D039642:Eukaryotic Initiation Factors; D014415:Tunicamycin
keywords: C. elegans; hypoxia; ischemia; translation factors