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PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1

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  • Raquel Requejo-Aguilar

    (Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC
    Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca)

  • Irene Lopez-Fabuel

    (Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC
    Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca)

  • Emilio Fernandez

    (Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC
    Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca)

  • Luis M. Martins

    (MRC Toxicology Unit, Hodgkin Building)

  • Angeles Almeida

    (Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC
    Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca)

  • Juan P. Bolaños

    (Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC
    Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca)

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.

Suggested Citation

  • Raquel Requejo-Aguilar & Irene Lopez-Fabuel & Emilio Fernandez & Luis M. Martins & Angeles Almeida & Juan P. Bolaños, 2014. "PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5514
    DOI: 10.1038/ncomms5514
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