title: Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells.
abstract: Peroxisome proliferator-activated receptor α, coactivator 1α (PGC-1α) is the master regulator of mitochondrial biogenesis. PGC-1α expression is under the control of the transcription factor, cAMP-responsive element-binding protein (CREB). In searching for candidate transcription factors that mediate mitochondrial stress-initiated mitochondria-to-nucleus signaling in the regulation of mitochondrial biogenesis, we assessed the effect of silencing CREB-regulated transcription co-activators (CRTC). CRTC isoforms are co-activators of CREB-regulated transcription by a CREB phosphorylation-independent pathway. Using cultured HepG2 cells and primary mouse hepatocytes, we determined that mitochondrial stress imposed by the complex I inhibitor rotenone elicited mitochondrial biogenesis, which was dependent on an induction of PGC-1α, which was inhibited by silencing PGC-1α. PGC-1α induction in response to rotenone was inhibited by silencing the expression of CRTC3, which blocked downstream mitochondria biogenesis. In contrast, silencing CRTC2 did not affect the induction of this pathway in response to rotenone. Thus, CRTC3 plays a selective role in mitochondrial biogenesis in response to rotenone.
authors.affiliation: University of Southern California Research Center for Liver Diseases, Southern California Research Center for Alcoholic, Liver and Pancreatic Disease, and Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Tin Aung
authors.initials: TA
authors.lastname: Than
authors.forename: Huan
authors.initials: H
authors.lastname: Lou
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
authors.forename: Sanda
authors.initials: S
authors.lastname: Win
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000818:Animals; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C555318:CRTC3 protein, mouse; C504923:Crtc2 protein, mouse; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D012402:Rotenone