ALDH2

ALDH2 Full Name

aldehyde dehydrogenase 2 family (mitochondrial)

ALDH2 Introduction

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that plays a critical role in the detoxification of aldehydes generated from alcohol metabolism, lipid peroxidation, and various biogenic amine pathways. ALDH2 is best known for its high-affinity oxidation of acetaldehyde, the toxic intermediate of ethanol metabolism, converting it to acetate with concomitant reduction of NAD⁺ to NADH. Beyond its role in alcohol metabolism, ALDH2 also metabolizes other toxic aldehydes including 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), and acrolein, which are produced during oxidative stress and lipid peroxidation. The enzyme is highly expressed in the liver, heart, brain, and kidney, with its mitochondrial localization placing it at the nexus of cellular energy metabolism, oxidative stress defense, and xenobiotic detoxification.

Figure 1. Alcohol metabolism and mechanisms of alcohol-induced liver injury associated with genetic polymorphisms in alcohol-metabolizing enzymes. Ethanol is metabolized in the liver via a two-step enzymatic process. Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH), and acetaldehyde is detoxified to acetate and water by ALDH.(Tadokoro T, et al. 2025)

Beyond Alcohol Metabolism: Oxidative Stress and Disease Modification

ALDH2 plays a critical role in metabolizing 4-hydroxy-2-nonenal (HNE), a major cytotoxic product of lipid peroxidation that accumulates in ischemic heart disease, non-alcoholic fatty liver disease (NAFLD), diabetes, and neurodegenerative disorders. ALDH2 activity is reduced under conditions of oxidative stress due to direct modification of Cys302 and other redox-sensitive residues. Pharmacological activation of ALDH2 with small molecules such as Alda-1 (a structurally specific activator that restores activity to ALDH2*2) has shown promise in preclinical models of myocardial infarction, stroke, diabetic cardiomyopathy, and Parkinson's disease. Conversely, ALDH2 deficiency exacerbates acetaminophen hepatotoxicity, doxorubicin cardiotoxicity, and cisplatin nephrotoxicity.

Genetic Architecture and Isoforms

The human ALDH2 gene is located on chromosome 12q24.12 and spans approximately 44 kb, containing 13 exons. A single major transcript encodes the 517-amino acid mitochondrial isoform (precursor protein of ~54 kDa, mature protein of ~50 kDa after cleavage). A minor splice variant (ALDH2v2) with an alternative C-terminus has been reported but shows limited catalytic activity. The closely related cytosolic isoform ALDH1A1 (aldehyde dehydrogenase 1 family member A1) oxidizes retinaldehyde to retinoic acid and metabolizes acetaldehyde with much lower affinity (Km ~30 μM vs. 0.2 μM for ALDH2). Several additional rare missense variants (e.g., p.Arg182Gln, p.Gly414Arg) have been identified in individuals with alcohol sensitivity or unexplained metabolic disorders, but their functional consequences remain incompletely characterized.

Alternate Names for ALDH2

ALDH2; aldehyde dehydrogenase 2 family (mitochondrial); aldehyde dehydrogenase, mitochondrial; ALDH class 2; liver mitochondrial ALDH; acetaldehyde dehydrogenase 2; nucleus-encoded mitochondrial aldehyde dehydrogenase 2; ALDM; ALDHI; ALDH-E2; MGC1806;

• 1.Tadokoro T, Oura K, Nakahara M, et al. Genetic Polymorphisms of ALDH2 and ADH1B in Alcohol-Induced Liver Injury: Molecular Mechanisms of Inflammation and Disease Progression in East Asian Populations. International Journal of Molecular Sciences, 2025, 26(17): 8328.