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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 HIF1a 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 HIF1a, sustaining increased cell proliferation. © 2014 Macmillan Publishers Limited.This work was funded by the Spanish Ministerio de Economia y Competitividad (to J.P.B., grant number SAF2013-41177-R), the Instituto de Salud Carlos III (to J.P.B., grant number RD12/0043/0021; to A.A., grant numbers PI12/00685 and RD12/0014/0007), Junta de Castilla y Leon (to J.P.B., SA003U13), the SP3-People-MC-ITN programme of the European Commission (to J.P.B., 608381 TINTIN), and the European Regional Development Fund. I.L.-F. is the recipient of a FPI Fellowship from the MINECO (Spain).Peer Reviewe

PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1