Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia

Karim Mekhail, Luis Rivero-Lopez, Mireille Khacho, Stephen Lee

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Biological evolution abides by an unbending rule obligating organisms to maintain energy equilibrium. Hypoxia reduces cellular energy supply and is thus thought to be deleterious. We report that cells have evolved pH-sensitive mechanisms to maintain energy equilibrium by lowering energy demand. We found that fermentation-induced acidosis allows hypoxic cells to maintain energy equilibrium and viability under hypoxia by restricting ribosomal biogenesis, the most energy-demanding cellular process. Acidosis triggers nucleolar condensation, decreases precursor rRNA synthesis, reduces the dynamic profile of the RNA polymerase I preinitiation factor UBF1 and its interaction with the promoter of rRNA genes (rDNA). These changes require the pH-dependent interaction of the statically detained von Hippel-Lindau tumor suppressor protein (VHL) with rDNA. This phenomenon is promoted by, but does not require, activation of the hypoxia-inducible factor (HIF), a transcription factor implicated in extracellular acidification, energy production and oxygen homeostasis. Abrogating this program by silencing VHL expression, competing rDNA-VHL interaction or preventing environmental acidification triggers energy starvation and cell death under hypoxia. Our data suggest that oxygen-starved cells maintain energy equilibrium by gauging the environmental concentration of H+ to statically detain VHL to nucleolar rDNA and restrict ribosome production. These findings also provide an explanation for the protective effect of acidosis in ischemic settings such as development, stroke and cancer.

Original languageEnglish (US)
Pages (from-to)2401-2413
Number of pages13
JournalCell Cycle
Volume5
Issue number20
DOIs
StatePublished - Oct 15 2006
Externally publishedYes

    Fingerprint

Keywords

  • Acidosis
  • FRAP
  • HIF
  • Hypoxia
  • IGS
  • Nucleolus
  • Ribosome
  • VHL
  • pH
  • rDNA

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this