Role of oxygen consumption in hypoxia protection by translation factor depletion

Barbara Scott, Chun Ling Sun, Xianrong Mao, Cong Yu, Bhupinder P.S. Vohra, Jeffrey Milbrandt, C. Michael Crowder

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)2283-2292
Number of pages10
JournalJournal of Experimental Biology
Volume216
Issue number12
DOIs
StatePublished - Jun 2013

Keywords

  • C. elegans
  • Hypoxia
  • Ischemia
  • Translation factors

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