Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury.
•Hepatotoxic agents including alcohol and high fat elevate nitroxidative stress.•Increased nitroxidative stress promotes post-translational protein modifications.•Post-translational protein modifications of many proteins lead to their inactivation.•Inactivation of mitochondrial proteins contributes to mitochondrial dysfunction.•Mitochondrial dysfunction contributes to necrotic or apoptotic tissue injury.
AA-AGE, acetaldehyde-derived advanced glycation end product; ACR, acrolein; AFLD, alcoholic fatty liver disease; AGE-albumin, advanced glycation end product-albumin adduct; ALDH2, mitochondrial low-Km aldehyde dehydrogenase 2; AMPK, AMP-activated protein kinase; APAP, acetaminophen; Complex I, NADH-dependent ubiquinone oxidoreductase; Complex III, ubiquinone cytochrome bc1 oxidoreductase; Complex IV, cytochrome c oxidase; Complex V, ATP synthase; CYP2E1, ethanol-inducible cytochrome P450 2E1 isozyme; DILI, drug-induced liver injury; DTT, dithiothreitol; eNOS, endothelial NOS; ER, endoplasmic reticulum; ERK, extracellular signal regulated protein kinase; ETC, electron transport chain; Gpx, glutathione peroxidase; GSH, glutathione; 4-HNE, 4-hydroxynonenal; HIF, hypoxia-inducible factor; ICDH, isocitrate dehydrogenase; I-kB, inhibitor protein of NF-κB; iNOS, inducible nitric oxide synthase; I/R, ischemia–reperfusion; JNK, c-Jun N-terminal protein kinase; Keap1, Kelch-like ECH-associated protein 1; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MDMA, 3,4-methylenedioxymethamphetamine; MGO, methylglyoxal; mito-CP, mitochondria-targeted carboxy-proxyl; mitoQ, mitochondria-targeted ubiquinone; MPT, mitochondrial permeability transition; mtGSH, mitochondrial glutathione; NAC, N-acetylcysteine; NAFLD, nonalcoholic fatty liver disease; NF-κB, nuclear factor-κB; NAPQI, N-acetyl-p-benzoquinone imine; NEL-adduct, N-ethyllysine adduct; nNOS, neuronal NOS; NO, nitric oxide; Nrf2, nuclear factor (erythroid-derived 2)-like 2; 4-ONE, 4-oxonon-2-enal; p38K, p38 protein kinase; PGC1α, peroxisomal proliferator activated receptor gamma coactivator-1α; PKC, protein kinase C; Prx, peroxiredoxin; PTEN, lipid phosphatase and tensin homolog; RAGE, receptor for advanced glycation end product; RNS, reactive nitrogen species; ROS, reactive oxygen species; S-NO-Cys, S-nitrosylated Cys; SAMe, S-adenosyl-methionine; SOD, superoxide dismutase; SREBP, sterol regulated element binding protein; Thiolase, 3-ketoacyl-CoA thiolase; TIMP, tissue inhibitor of metalloproteinase 3; TPP+, triphenylphosphonium cation.; Nitroxidative stress; Redox; Post-translational modifications; Mitochondrial proteins; Mitochondrial dysfunction; Tissue injury