Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications

Abstract

Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.

Emodin Ameliorates Ethanol-Induced Fatty Liver Injury in Mice

“…Oxidation of unsaturated fatty acids increases lipid peroxidation products that ultimately lead to liver fibrosis by activating stellate cells [23]. CYP2E1 is known to increase ROS levels, which may modify the function of various proteins, contributing to more severe liver damage [24]. In our present study, fatty liver and oxidative stress were attenuated in emodin-treated mice.…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…However, markedly elevated amounts of acetaldehyde can be accumulated after inhibition of ALDH2 with its chemical inhibitors such as disulfiram (Antabuse ® ) and cyanamide. Alternatively, acetaldehyde can be elevated after suppression of mitochondrial ALDH2 through various forms of PTM following exposure to many hepatotoxic agents such as alcohol (Moon et al, 2006;Venkatraman, Landar, Davis, Ulasova, et al, 2004), APAP, high fat, anticancer drugs, toxic substances, and other pathological conditions, as reviewed (Song, Akbar, et al, 2014;Song et al, 2013Song et al, , 2011. In fact, accumulated NADH and acetaldehyde caused by using either disulfiram (Antabuse ® ) or cyanamide caused fat accumulation in alcohol-exposed hepatoma cells H4EIIE cells or rodents (Kato, Kawase, Alderman, Inatomi, & Lieber, 1990;You, Fischer, Deeg, & Crabb, 2002;You, Matsumoto, Pacold, Cho, & Crabb, 2004).…”

Reactive aldehyde-scavenging enzyme activities in atherosclerotic plaques of cigarette smokers and nonsmokers

“…In this regard, it is possible that oxidant compounds present in CS and/or produced as a result of CS-tissue interaction may impact with the ALDH active site leading to enzymatic inactivation. Indeed, critical cysteine residues of ALDH are susceptible to oxidant damage resulting in enzyme inactivation [19]. Another possibility is that some aldehydic compounds of CS exert inhibitory effects on ALDH; a candidate may be acetaldehyde, formed by pyrolysis from natural tobacco polysaccharides including cellulose [20], after transformation into acetaldehyde hydrate, which represents the ALDH inhibitor [21].…”