Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR

Zandra E. Walton, Chirag H. Patel, Rebekah C. Brooks, Yongjun Yu, Arig Ibrahim-Hashim, Malini Riddle, Alessandra Porcu, Tianying Jiang, Brett L. Ecker, Feven Tameire, Constantinos Koumenis, Ashani T. Weeraratna, David K. Welsh, Robert Gillies, James C. Alwine, Lin Zhang, Jonathan D. Powell, Chi V. Dang

Research output: Contribution to journalArticlepeer-review

Abstract

Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.

Original languageEnglish (US)
Pages (from-to)72-87.e32
JournalCell
Volume174
Issue number1
DOIs
StatePublished - Jun 28 2018

Keywords

  • RHEB
  • acidity
  • cancer
  • circadian
  • clock
  • hypoxia
  • hypoxia-inducible factor
  • lysosome
  • mTOR
  • pH

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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