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MITOCHONDRIAL Akt REGULATION OF HYPOXIC METABOLIC REPROGRAMMING

ABSTRACT: Hypoxia is a driver of aggressive tumor behavior, but the mechanisms are not completely understood. In a global phosphoproteomics screen, we now demonstrate that hypoxia induces the recruitment of Akt2 to tumor mitochondria, and Akt phosphorylation of pyruvate dehydrogenase kinase (PDK1) on Thr346. In turn, Akt-phosphorylated PDK1 shuts off oxidative phosphorylation via phosphorylation of the pyruvate dehydrogenase complex, and reprograms tumor metabolism towards glycolysis. Akt-phosphorylation of PDK1 is required to prevent autophagy, maintain cell viability and support tumor cell proliferation in hypoxia, in vivo. Therefore, mitochondrial Akt is a pathophysiologic switch for tumor adaptation in hypoxia.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dario C. Altieri

PROVIDER: MSV000079671 | MassIVE | Wed Apr 20 18:46:00 BST 2016

SECONDARY ACCESSION(S): PXD004024

REPOSITORIES: MassIVE

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