Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an “actionable” therapeutic target in cancer. •A pool of active Akt is recruited to tumor mitochondria during hypoxia•Mitochondrial Akt phosphorylates PDK-1 in hypoxia on a T346 site•Akt-PDK1 activation maintains tumor cell proliferation in hypoxia•PDK1 phosphorylation by Akt is a negative prognostic factor in gliomas Chae et al. identify a pool of phosphorylated Akt that translocates to the mitochondria during hypoxia. Mitochondrial Akt phosphorylates PDK1, which supports cell survival and proliferation during hypoxia, and elevated Akt-dependent phosphorylation of PDK1 correlates with reduced survival of glioma patients.