Aldehyde dehydrogenase, mitochondrial (ALDH2)

Human mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme located in the mitochondrial matrix that plays a central role in the detoxification of both exogenous and endogenous aldehydes [1.1.1, 1.3.3]. It is most prominently known for its role in the second step of ethanol metabolism, where it oxidizes toxic acetaldehyde into acetate [1.2.1, 1.3.3]. Beyond alcohol metabolism, ALDH2 protects cells from oxidative stress by metabolizing reactive lipid peroxidation products like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) [1.2.3, 1.2.5]. A common genetic polymorphism, ALDH2*2 (rs671), prevalent in approximately 35-45% of East Asian populations, results in a nearly inactive enzyme, causing the alcohol flushing syndrome and significantly increasing the risk of esophageal cancer among alcohol consumers [1.2.1, 1.4.1]. ALDH2 also functions as a reductase to bioactivate nitroglycerin into nitric oxide, making it essential for the drug's vasodilatory effects [1.3.2, 1.4.3]. Therapeutic targeting of ALDH2 includes the use of inhibitors like disulfiram to induce alcohol aversion in patients with alcohol use disorder [1.2.1, 1.2.4]. Conversely, small-molecule activators such as Alda-1 are being investigated for their potential to treat myocardial infarction, heart failure, and neurodegenerative diseases by enhancing the clearance of toxic aldehydes [1.1.1, 1.2.3].

Other names

ALDH-E2ALDHIALDMAldehyde dehydrogenase 2 family memberMitochondrial aldehyde dehydrogenase 2

Irreversible inhibition of enzyme activity to prevent acetaldehyde metabolism (e.g., disulfiram); allosteric activation to enhance detoxification of reactive aldehydes (e.g., Alda-1); and reductive bioactivation of organic nitrates (e.g., nitroglycerin) [1.2.1, 1.2.4, 1.3.2].