title: Chronic ethanol consumption induces mitochondrial protein acetylation and oxidative stress in the kidney.
abstract: In this study, we present the novel findings that chronic ethanol consumption induces mitochondrial protein hyperacetylation in the kidney and correlates with significantly increased renal oxidative stress. A major proteomic footprint of alcoholic liver disease (ALD) is an increase in hepatic mitochondrial protein acetylation. Protein hyperacetylation has been shown to alter enzymatic function of numerous proteins and plays a role in regulating metabolic processes. Renal mitochondrial targets of hyperacetylation include numerous metabolic and antioxidant pathways, such as lipid metabolism, oxidative phosphorylation, and amino acid metabolism, as well as glutathione and thioredoxin pathways. Disruption of protein lysine acetylation has the potential to impair renal function through metabolic dysregulation and decreased antioxidant capacity. Due to a significant elevation in ethanol-mediated renal oxidative stress, we highlight the acetylation of superoxide dismutase, peroxiredoxins, glutathione reductase, and glutathione transferase enzymes. Since oxidative stress is a known factor in ethanol-induced nephrotoxicity, we examined biochemical markers of protein hyperacetylation and oxidative stress. Our results demonstrate increased protein acetylation concurrent with depleted glutathione, altered Cys redox potential, and the presence of 4-HNE protein modifications in our 6-week model of early-stage alcoholic nephrotoxicity. These findings support the hypothesis that ethanol metabolism causes an influx of mitochondrial metabolic substrate, resulting in mitochondrial protein hyperacetylation with the potential to impact mitochondrial metabolic and antioxidant processes.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Roy
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Coughlan
authors.affiliation: Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.affiliation: Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Colin T
authors.initials: CT
authors.lastname: Shearn
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Roede
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Kristofer.fritz@ucdenver.edu.
authors.forename: Kristofer S
authors.initials: KS
authors.lastname: Fritz
mesh_terms: D000107:Acetylation; D000437:Alcoholism / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000447:Aldehydes / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000431:Ethanol / Q000009:adverse effects*; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D054464:Peroxiredoxins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000596:Amino Acids; D024101:Mitochondrial Proteins; D000431:Ethanol; D054464:Peroxiredoxins; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal; Acetylation; Ethanol; Glutathione; Kidney; Oxidative stress