PMID- 25099937 OWN - NLM STAT- MEDLINE DCOM- 20151130 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 8 DP - 2014 TI - Ethanol suppresses PGC-1alpha expression by interfering with the cAMP-CREB pathway in neuronal cells. PG - e104247 LID - 10.1371/journal.pone.0104247 [doi] LID - e104247 AB - 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-1alpha) 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-1alpha expression. We report that ethanol suppresses PGC-1alpha 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-1alpha 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-1alpha gene. Accordingly, we found PGC-1alpha 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-1alpha. Ethanol-mediated decrease in PGC-1alpha 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-1alpha. FAU - Liu, Zilong AU - Liu Z AD - 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. FAU - Liu, Yongping AU - Liu Y AD - Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Gao, Rui AU - Gao R AD - Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Li, Haixia AU - Li H AD - Department of Internal Medicine/Gastroenterology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Dunn, Tiffany AU - Dunn T AD - Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Wu, Ping AU - Wu P AD - Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Smith, Robert G AU - Smith RG AD - Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Sarkar, Partha S AU - Sarkar PS AD - 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. FAU - Fang, Xiang AU - Fang X AD - Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America. LA - eng GR - K02 NS081000/NS/NINDS NIH HHS/United States GR - 1K02NS081000-01A1/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140806 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (CREB1 protein, human) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (PPARGC1A protein, human) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Transcription Factors) RN - 3K9958V90M (Ethanol) RN - E0399OZS9N (Cyclic AMP) RN - K676NL63N7 (Rolipram) SB - IM EIN - PLoS One. 2014;9(9):e108118 MH - Cell Line, Tumor MH - Cyclic AMP/genetics/*metabolism MH - Cyclic AMP Response Element-Binding Protein/genetics/*metabolism MH - Ethanol/*pharmacology MH - Gene Expression Regulation/*drug effects MH - Humans MH - Neurons/cytology/*metabolism MH - Oxygen Consumption/drug effects/genetics MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Response Elements MH - Rolipram/pharmacology MH - Second Messenger Systems/*drug effects/genetics MH - Transcription Factors/*biosynthesis/genetics MH - Transcription, Genetic/drug effects/genetics PMC - PMC4123904 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/08/08 06:00 MHDA- 2015/12/15 06:00 PMCR- 2014/08/06 CRDT- 2014/08/08 06:00 PHST- 2014/03/10 00:00 [received] PHST- 2014/06/25 00:00 [accepted] PHST- 2014/08/08 06:00 [entrez] PHST- 2014/08/08 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2014/08/06 00:00 [pmc-release] AID - PONE-D-14-10535 [pii] AID - 10.1371/journal.pone.0104247 [doi] PST - epublish SO - PLoS One. 2014 Aug 6;9(8):e104247. doi: 10.1371/journal.pone.0104247. eCollection 2014.