PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1

Nat Commun. 2014 Jul 24:5:4514. doi: 10.1038/ncomms5514.

Abstract

PTEN-induced kinase-1 (PINK1) is a Ser/Thr kinase implicated in familial early-onset Parkinson's disease, and was first reported as a growth suppressor. PINK1 loss-of-function compromises both mitochondrial autophagy and oxidative phosphorylation. Here we report that PINK1 deficiency triggers hypoxia-inducible factor-1α (HIF1α) stabilization in cultured Pink1(-/-) mouse embryonic fibroblasts and primary cortical neurons as well as in vivo. This effect, mediated by mitochondrial reactive oxygen species, led to the upregulation of the HIF1 target, pyruvate dehydrogenase kinase-1, which inhibits PDH activity. Furthermore, we show that HIF1α stimulates glycolysis in the absence of Pink1, and that the promotion of intracellular glucose metabolism by HIF1α stabilization is required for cell proliferation in Pink1(-/-) mice. We propose that loss of Pink1 reprograms glucose metabolism through HIF1α, sustaining increased cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Enzymes / genetics
  • Enzymes / metabolism
  • Fibroblasts / metabolism
  • Glucose / metabolism*
  • Glucose Transporter Type 1 / metabolism
  • Glucose Transporter Type 3 / metabolism
  • Glycolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Neurons / metabolism
  • Protein Kinases / deficiency
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Reactive Oxygen Species / metabolism

Substances

  • Enzymes
  • Glucose Transporter Type 1
  • Glucose Transporter Type 3
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • Slc2a1 protein, mouse
  • Slc2a3 protein, mouse
  • Protein Kinases
  • PTEN-induced putative kinase
  • Glucose