PI3K/AKT signaling regulates bioenergetics in immortalized hepatocytes |
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| Institution: | 1. Pharmacology and Pharmaceutical Sciences, School of Pharmacy;2. Biochemistry and Molecular Biology;3. Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA;1. Livestock Research Institute, COA, Tainan, Taiwan;2. Department of Animal Science, National Chung Hsing University, Taichung, Taiwan;3. Graduate Institute of Veterinary Pathology, National Chung-Hsing University, Taichung, Taiwan;4. Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan;5. Core Laboratory for Stem Cell Research, Medical Research Department, China Medical University Hospital, Taichung, Taiwan;6. Department of Bioinfomatics and Medical Engineering, Asia University, Taichung, Taiwan;1. Toyo Feather Industry Co. Ltd., 2-26-5, Fuchinobe, Chuo Ward, Sagamihara, Kanagawa 252-0206, Japan;2. Research Institute for Sustainable Humanosphere, Kyoto University, Uji, Kyoto 611-0011, Japan;3. Department of Forest Microbiology, Forestry and Forest Products Research Institute, Tsukuba, Ibaraki 305-8687, Japan;4. Center for Cultural Heritage Studies, Kyoto University, Yoshida-Honmachi, Kyoto 606-8501, Japan;1. Institute of Basic Medicine Science, Xi’an Medical University, Xi’an 710021, China;2. Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;3. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China;1. Department of Colorectal Surgery, Wenzhou Center Hospital, Wenzhou, 325000, China;2. Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China;3. Gastrology Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China;1. Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, Korea;2. Department of Anatomy and Cell Biology, Kangwon National University School of Medicine, Chuncheon 200-701, Korea;3. Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea;4. Institute of Medical Sciences, Department of Urology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea;5. Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus) Pukyong National University, Busan 608-737, Korea;6. Department of Microbiology, Inje University College of Medicine, Busan 614-735, Korea |
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| 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. |
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