title: PI3K/AKT signaling regulates bioenergetics in immortalized hepatocytes.
abstract: Regulation of cellular bioenergetics by PI3K/AKT signaling was examined in isogenic hepatocyte cell lines lacking the major inhibitor of PI3K/AKT signaling, PTEN (phosphatase and tensin homolog deleted on chromosome 10). PI3K/AKT signaling was manipulated using the activator (IGF-1) and the inhibitor (LY 294002) of the PI3K/AKT pathway. Activation of PI3K/AKT signaling resulted in an enhanced anaerobic glycolysis and mitochondrial respiration. AKT, when phosphorylated and activated, translocated to mitochondria and localized within the membrane structure of mitochondria, where it phosphorylated a number of mitochondrial-resident proteins including the subunits α and β of ATP synthase. Inhibition of GSK3β by either phosphorylation by AKT or lithium chloride resulted in activation of pyruvate dehydrogenase, i.e., a decrease in its phosphorylated form. AKT-dependent phosphorylation of ATP synthase subunits α and β resulted in an increased complex activity. AKT translocation to mitochondria was associated with an increased expression and activity of complex I. These data suggest that the mitochondrial signaling pathway AKT/GSK3β/PDH, AKT-dependent phosphorylation of ATP synthase, and upregulation of mitochondrial complex I expression and activity are involved in the control of mitochondrial bioenergetics by increasing substrate availability and regulating the mitochondrial catalytic/energy-transducing capacity.
authors: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, Los Angeles, CA 90089 United States.
authors: Chen
authors: C
authors: Li
authors: Yang
authors: Y
authors: Li
authors: Lina
authors: L
authors: He
authors: Amit R
authors: AR
authors: Agarwal
authors: Ni
authors: N
authors: Zeng
authors: Enrique
authors: E
authors: Cadenas
authors: Bangyan L
authors: BL
authors: Stiles
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000235:genetics*; D005609:Free Radicals / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012119:Respiration; D015398:Signal Transduction
chemical_list: D005609:Free Radicals; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D025261:Mitochondrial Proton-Translocating ATPases
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