Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR

Cell. 2018 Jun 28;174(1):72-87.e32. doi: 10.1016/j.cell.2018.05.009. Epub 2018 May 31.

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.

Keywords: RHEB; acidity; cancer; circadian; clock; hypoxia; hypoxia-inducible factor; lysosome; mTOR; pH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • CLOCK Proteins / metabolism
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Hypoxia*
  • Cells, Cultured
  • Circadian Clocks* / drug effects
  • Culture Media / chemistry
  • Eukaryotic Initiation Factors
  • Hydrogen-Ion Concentration
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Ras Homolog Enriched in Brain Protein / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Transcriptome / drug effects
  • Tuberous Sclerosis Complex 2 Protein / deficiency
  • Tuberous Sclerosis Complex 2 Protein / genetics

Substances

  • Amino Acids, Dicarboxylic
  • Carrier Proteins
  • Cell Cycle Proteins
  • Culture Media
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Phosphoproteins
  • RNA, Small Interfering
  • Ras Homolog Enriched in Brain Protein
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • CLOCK Proteins
  • Clock protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • oxalylglycine