Editors' ChoiceCell Biology

Lysosomes on an acid trip

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Sci. Signal.  24 Jul 2018:
Vol. 11, Issue 540, eaau8386
DOI: 10.1126/scisignal.aau8386

Acidic environments cause lysosomes to redistribute to the cell periphery, suppressing mTORC1, translation, and circadian oscillations.

Disruptions in circadian oscillations are linked to increased cancer incidence. Solid tumors are generally hypoxic, leading to increased activity of hypoxia-inducible factors (HIFs), enhanced anaerobic glycolysis, and acidification of the surrounding environment. Walton et al. investigated the link between hypoxia-induced metabolic disturbances and circadian rhythms. In human osteosarcoma U2-OS cells, hypoxia suppressed the activity of transcriptional reporters for various clock proteins, an effect that was reversed by buffering against acidification, knockdown of HIF-1α and HIF-2α, or inhibition of glycolysis. RNA sequencing confirmed that mRNAs encoding clock proteins and regulators did not show oscillatory changes (or showed less pronounced oscillatory changes) in abundance in cells cultured in acidic medium or in cells in which HIFs were stabilized. Low pH inhibited protein translation and mTORC1, a multiprotein complex that regulates protein translation through 4EBP1 (eukaryotic translation initiation factor 4E–binding protein 1). The decrease in mTORC1 activity in cells in acidic medium was rescued by buffering and was independent of amino acid sensing. The GTP-binding protein RHEB, which promotes the activation of mTORC1, was localized to the perinuclear region. Acidic medium triggered the redistribution of lysosomes from their normal perinuclear location to the periphery of cells, preventing the colocalization of mTORC1 at lysosomes with RHEB. Consistent with these observations, mTORC1 activity was increased in some tumor types in mice given water supplemented with sodium bicarbonate to raise intratumoral pH, an effect not seen in mice given unsupplemented water. These results suggest that hypoxia suppresses circadian rhythms because of the metabolic changes caused by HIFs, rather than the binding of HIF-1α to promoters of clock genes as has been suggested by previous studies.

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