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The Journal of pharmacology and experimental therapeutics

Aberrant histone acetylation promotes mitochondrial respiratory suppression in the brain of alcoholic rats.


PMID 25406171

Abstract

The acetylation of histone proteins in the core of DNA regulates gene expression, including those affecting mitochondria. Both histone acetylation and mitochondrial deficit have been implicated in neuronal damage associated with drinking problems. Many alcoholics will repeat unsuccessful attempts at abstaining, developing a pattern of repeated drinking and withdrawal. We investigated whether aberrant histone acetylation contributes to mitochondrial and cellular damage induced by repeated ethanol withdrawal (EW). We also investigated whether this effect of histone acetylation involves let-7f, a small noncoding RNA (microRNA). Male rats received two cycles of an ethanol/control diet (7.5%, 4 weeks) and withdrawal. Their prefrontal cortex was collected to measure the mitochondrial respiration and histone acetylation using extracellular flux (XF) real-time respirometry and gold immunostaining, respectively. Separately, HT22 (mouse hippocampal) cells received two cycles of ethanol exposure (100 mM, 20 hours) and withdrawal. Trichostatin A (TSA) as a histone acetylation promoter and let-7f antagomir were applied during withdrawal. The mitochondrial respiration, let-7f level, and cell viability were assessed using XF respirometry, quantitative polymerase chain reaction, TaqMan let-7f primers, and a calcein-acetoxymethyl assay, respectively. Repeated ethanol withdrawn rats showed a more than 2-fold increase in histone acetylation, accompanied by mitochondrial respiratory suppression. EW-induced mitochondrial respiratory suppression was exacerbated by TSA treatment in a manner that was attenuated by let-7f antagomir cotreatment. TSA treatment did not alter the increasing effect of EW on the let-7f level but dramatically exacerbated the cell death induced by EW. These data suggest that the multiple episodes of withdrawal from chronic ethanol impede mitochondrial and cellular integrity through upregulating histone acetylation, independent of or additively with let-7f.