title: Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain.
abstract: Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.
authors: Department of Systems Biology and the Harvard University Wyss Institute of Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02115, USA.
authors: William T
authors: WT
authors: Senapedis
authors: Caleb J
authors: CJ
authors: Kennedy
authors: Patrick M
authors: PM
authors: Boyle
authors: Pamela A
authors: PA
authors: Silver
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D000071245:Mitochondrial Uncoupling Proteins; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D021381:Protein Transport / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D000071247:Uncoupling Protein 3
chemical_list: D045222:Electron Transport Chain Complex Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C116584:SLC25A14 protein, human; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8