Hypoxia-induced energy stress regulates mRNA translation and cell growth

Oxygen (O-2) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O-2 in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including elF2 alpha, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70(S6K), and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G, arrest. Together, elF2 alpha, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O-2 conditions.