title: Ethanol suppresses PGC-1α expression by interfering with the cAMP-CREB pathway in neuronal cells.
abstract: Alcohol intoxication results in neuronal apoptosis, neurodegeneration and manifest with impaired balance, loss of muscle coordination and behavioral changes. One of the early events of alcohol intoxication is mitochondrial (Mt) dysfunction and disruption of intracellular redox homeostasis. The mechanisms by which alcohol causes Mt dysfunction, disrupts cellular redox homeostasis and triggers neurodegeneration remains to be further investigated. Proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) plays critical roles in regulating Mt biogenesis and respiration, cellular antioxidant defense mechanism, and maintenance of neuronal integrity and function. In this study, we sought to investigate whether alcohol causes Mt dysfunction and triggers neurodegeneration by suppressing PGC-1α expression. We report that ethanol suppresses PGC-1α expression, and impairs mitochondrial function and enhances cellular toxicity in cultured neuronal cell line and also in human fetal brain neural stem cell-derived primary neurons. Moreover, we report that cells over-expressing exogenous PGC-1α or treated with Rolipram, a selective phosphodiesterase-4 inhibitor, ameliorate alcohol-induced cellular toxicity. Further analysis show that ethanol decreases steady-state intracellular cAMP levels, and thus depletes phosphorylation of cAMP-response element binding protein (p-CREB), the key transcription factor that regulates transcription of PGC-1α gene. Accordingly, we found PGC-1α promoter activity and transcription was dramatically repressed in neuronal cells when exposed to ethanol, suggesting that ethanol blunts cAMP→CREB signaling pathway to interfere with the transcription of PGC-1α. Ethanol-mediated decrease in PGC-1α activity results in the disruption of Mt respiration and function and higher cellular toxicity. This study might lead to potential therapeutic intervention to ameliorate alcohol-induced apoptosis and/or neurodegeneration by targeting PGC-1α.
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine/Gastroenterology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Haixia
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Dunn
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Smith
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Sarkar
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020218:Response Elements; D020889:Rolipram / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D000431:Ethanol; D000242:Cyclic AMP; D020889:Rolipram
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