Post-translational regulation of mTOR complex 1 in hypoxia and reoxygenation.

The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth and proliferation in response to various upstream signals. Hypoxia has been shown to exert a strong inhibitory effect on mTORC1 activity. Various mechanisms involving gene transcription have been proposed to mediate the effect of hypoxia on mTORC1 activity. Here we show that oxygen concentrations regulate mTORC1 activity in a highly dynamic manner. The rapid response of mTORC1 to changes in oxygen concentrations was not mediated by the HIF transcription factor or its transcriptional targets, REDD1 and BNIP3. Interestingly, we observed that the rapid response of mTORC1 activity to changes in oxygen concentrations is independent of transcription and new protein synthesis. This suggests a post-translational regulation mTORC1 activity in hypoxia and reoxygenation. We also provide evidence that hypoxia does not regulate mTORC1 via the TSC1/2 or Ragulator pathways but directly at the level of mTORC1. In conclusion, our results suggest that mTORC1 can respond rapidly to changes in oxygen concentrations via a post-translational mechanism that may involve a heme containing protein.