title: Autophagy in premature senescent cells is activated via AMPK pathway.
abstract: Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. In this study, we show that the activity of autophagy increases in H(2)O(2) or RasV12-induced senescent fibroblasts. Inhibiting autophagy promotes cell apoptosis in senescent cells, suggesting that autophagy activation plays a cytoprotective role. Furthermore, our data indicate that the increase of autophagy in senescent cells is linked to the activation of transcription factor FoxO3A, which blocks ATP generation by transcriptionally up-regulating the expression of PDK4, an inhibitor of pyruvate dehydrogenase complex, thus leading to AMPK activation and mTOR inhibition. These findings suggest a novel mechanism by which FoxO3A factors can activate autophagy via metabolic alteration.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
authors.forename: Liujing
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
authors.forename: Bushan
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Mao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases