Ethanol suppresses PGC-1α expression by interfering with the cAMP-CREB pathway in neuronal cells

Zilong Liu, Yongping Liu, Rui Gao, Haixia Li, Tiffany Dunn, Ping Wu, Robert G. Smith, Partha Sarkar, Xiang Fang

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere104247
JournalPLoS One
Volume9
Issue number8
DOIs
StatePublished - Aug 6 2014

Fingerprint

Ethanol
alcohols
neurons
ethanol
Alcohols
Transcription
Alcoholic Intoxication
Toxicity
cytotoxicity
transcription (genetics)
Oxidation-Reduction
Homeostasis
poisoning
Phosphodiesterase 4 Inhibitors
homeostasis
Rolipram
Apoptosis
Cell Respiration
apoptosis
Cyclic AMP Response Element-Binding Protein

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ethanol suppresses PGC-1α expression by interfering with the cAMP-CREB pathway in neuronal cells. / Liu, Zilong; Liu, Yongping; Gao, Rui; Li, Haixia; Dunn, Tiffany; Wu, Ping; Smith, Robert G.; Sarkar, Partha; Fang, Xiang.

In: PLoS One, Vol. 9, No. 8, e104247, 06.08.2014.

Research output: Contribution to journalArticle

Liu, Zilong ; Liu, Yongping ; Gao, Rui ; Li, Haixia ; Dunn, Tiffany ; Wu, Ping ; Smith, Robert G. ; Sarkar, Partha ; Fang, Xiang. / Ethanol suppresses PGC-1α expression by interfering with the cAMP-CREB pathway in neuronal cells. In: PLoS One. 2014 ; Vol. 9, No. 8.
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