title: PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1.
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.
authors: 1] Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors: Raquel
authors: R
authors: Requejo-Aguilar
authors: 1] Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors: Irene
authors: I
authors: Lopez-Fabuel
authors: 1] Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors: Emilio
authors: E
authors: Fernandez
authors: MRC Toxicology Unit, Hodgkin Building, Leicester LE1 9HN, UK.
authors: Luis M
authors: LM
authors: Martins
authors: 1] Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors: Angeles
authors: A
authors: Almeida
authors: 1] Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, 37007 Salamanca, Spain.
authors: Juan P
authors: JP
authors: Bolaños
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004798:Enzymes; D005947:Glucose; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011494:Protein Kinases; D017382:Reactive Oxygen Species; D000099202:PTEN-Induced Putative Kinase; C497443:Hif1a protein, mouse; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse