Role of oxygen consumption in hypoxia protection by translation factor depletion

Abstract

SUMMARYThe 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.

Ageing and hypoxia cause protein aggregation in mitochondria

“…Further, translational suppression has been shown to confer resistance to hypoxic death and therefore if mitochondrial aggregates were deleterious, cycloheximide might be associated with reduced aggregates. 19,20 However, cycloheximide at concentrations previously shown to inhibit translation to 35% (1 mg/ml) and 20% (3 mg/ml) of baseline did not reduce aggregates load; 19 rather, it dose-dependently increased it (Supplementary Figure S3). Our findings demonstrate that aggregation increases with worsening hypoxic stress, that the aggregate load appears to be, in part, reversible, and that cytoplasmic translational inhibition at a level previously shown to protect from hypoxic injury actually increases aggregation.…”

Mitochondrial Proteostatic Collapse Leads to Hypoxic Injury

“…Feeding RNAi was performed as previously reported [32], however, LB was used instead of 2xYT and tetracycline was not used.…”

Stress-mediated translational control in cancer cells

“…Given that hypoxia lowers ATP production [56] and that mRNA translation is a highly energyconsuming process [5], its rate needs to be properly reduced to preserve energy under conditions of low oxygen levels [57]. Such a response is critical to promote survival of both tumor and normal cells subjected to prolonged hypoxia [58,59]. When considering how hypoxia might impact overall translation rates, it is important to distinguish the effects of moderate (0.5%-1% O 2 ) from those of severe hypoxia (≤0.02% O 2 ).…”

“…Indeed, forced expression of PHD2 attenuates eEF2 phosphorylation under acute hypoxia through an unknown mechanism [86]. The fine control of eEF2 activity under hypoxia may be important for tumor cell survival, as it was shown that targeted inhibition of eEF2 in normal tissues provides protection against hypoxia in vivo [59]. How this facilitates cell survival is unknown, and remains to be demonstrated in tumor cells.…”