A lactate-induced response to hypoxia

Cell. 2015 Apr 23;161(3):595-609. doi: 10.1016/j.cell.2015.03.011. Epub 2015 Apr 16.


Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Lactic Acid / metabolism*
  • MAP Kinase Signaling System
  • Neovascularization, Pathologic / metabolism
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism
  • Oxygen / metabolism
  • Protein Binding
  • raf Kinases / metabolism


  • Intracellular Signaling Peptides and Proteins
  • NDRG3 protein, human
  • Nerve Tissue Proteins
  • Lactic Acid
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • raf Kinases
  • Oxygen