PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1

• Published in: Nature communications 2014-07, Vol.5 (1), p.4514
• Main Authors: Requejo-Aguilar, Raquel, Lopez-Fabuel, Irene, Fernandez, Emilio, Martins, Luis M., Almeida, Angeles, Bolaños, Juan P.
• Format: Article
• Language: English
• Subjects: 14; 14/19; 38; 38/1; 38/109; 38/22; 38/88; 38/89; 38/91; 42; 631/136/2091; 631/136/2435; 631/378/340; 631/443/319; 64; 64/110; 64/60; 96; 96/106; 96/2; 96/31; 96/47; Animals; Cell Proliferation; Cells, Cultured; Enzymes - genetics; Enzymes - metabolism; Fibroblasts - metabolism; Glucose - metabolism; Glucose Transporter Type 1 - metabolism; Glucose Transporter Type 3 - metabolism; Glycolysis; Humanities and Social Sciences; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; multidisciplinary; Neurons - metabolism; Protein Kinases - deficiency; Protein Kinases - genetics; Protein Kinases - metabolism; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723
• DOI: 10.1038/ncomms5514

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. Loss of function of the kinase PINK1 is associated with familial early-onset Parkinson’s disease and impaired clearance of damaged mitochondria. Here the authors show that the resulting oxidative stress activates the hypoxia regulator HIF1α, resulting in increased glycolysis and cell proliferation.