Aberrant Histone Acetylation Promotes Mitochondrial Respiratory Suppression in the Brain of Alcoholic Rats

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 Repeated ethanol withdrawn rats showed a more than 2-fold increase in histone acetylation, accompanied by mitochondrial respiratory suppression.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.

Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c‐Fos Protein Expression in Male Rats

“…For example, EtOH intoxication‐induced reductions in neurogenesis impact the dentate gyrus, while glial responses and reactive (increased) neurogenesis occur during protracted withdrawal (Geil et al., ; Kelso et al., ; Marshall et al., ). A relationship between aberrant histone acetylation and impairments in mitochondrial respiration also supports a link between histone modifications and neurodegenerative processes (Jung and Metzger, ). Functionally, induction of long‐term potentiation in hippocampal cornus ammonis (CA) 1 neurons is potently inhibited by EtOH (Durand and Carlen, ).…”

A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

“…According to these findings, it was observed that intermittent ethanol treatment caused changes in the acetylation of histones H3 and H4 in the prefrontal cortex, NAc and striatum, suggesting chromatin remodelling changes, which may mediate long-term alterations, contributing to mitochondrial and cellular damage (Jung and Metzger 2015). Taken together, these results seem to evidence that alcohol can sensitise the mesolimbic and mesocortical dopamine pathways to cause changes in dopaminergic and glutamatergic signalling, which may affect the remodelling and functions of the brain (Pascual et al 2009).…”

Alcohol consumption during adolescence: A link between mitochondrial damage and ethanol brain intoxication

“…Complementary studies support mitochondrial dysfunction since increased lipid peroxidation, and mitochondrial protein oxidation is detected in the cortex, hippocampus and mainly in the cerebellum (Jung, Yan, Forster, & Simpkins, ). In the latter, a bioenergetics deficit is detected, indicated by reduced expression of the mitochondrial complex V (Jung and Metzger, ) and ATP production in neurons (Follesa et al, ). Finally, the higher calcium concentrations associated with increased oxidative stress induce mPTP opening in a permanent and nontransient manner (Jung et al, ), and activate pro‐apoptotic genes (Hashimoto and Wiren, ).…”

“…As discussed in the previous section and summarized in Table , ethanol exposure induces negative changes that affect mitochondrial function. These alterations include (a) increased ROS production (Albano, ; Das and Vasudevan, ), (b) calcium deregulation, (Giorgi et al, ), (c) mitochondrial respiration impairment (Bustamante et al, ; Jung and Metzger, ; Karadayian et al, ), (4) reduced ATP production (Jung, ; Ramachandran et al, ; Reddy et al, ); and finally, (5) mPTP opening (Jung, ; Karadayian et al, ). All these events, in turn, could result in neuronal death (Bustamante et al, ; Heaton et al, ; Lacaille et al, ).…”