Aldehyde dehydrogenase, mitochondrial (ALDH2) (ALDH2)

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme located in the mitochondrial matrix, primarily known for its role in the second stage of ethanol metabolism. It catalyzes the oxidation of acetaldehyde, a toxic and carcinogenic intermediate, into the less harmful acetate [1, 3, 10]. Beyond alcohol metabolism, ALDH2 serves as a vital detoxifying agent for reactive aldehydes generated during lipid peroxidation, such as 4-hydroxy-2-nonenal (4-HNE), which are implicated in oxidative stress and cellular damage [2, 6, 11]. A common genetic polymorphism, ALDH2*2 (rs671), results in a nearly inactive enzyme and is highly prevalent in East Asian populations, leading to alcohol flushing syndrome and increased susceptibility to esophageal cancer and cardiovascular diseases [5, 14, 16]. In clinical practice, ALDH2 is targeted by the inhibitor disulfiram to treat alcohol use disorder by causing an accumulation of acetaldehyde and subsequent unpleasant physiological reactions [13, 17, 19]. Emerging therapeutic strategies focus on ALDH2 activators, such as Alda-1, which aim to enhance the enzyme's activity to protect against ischemia-reperfusion injury in the heart and brain, as well as neurodegenerative conditions like Alzheimer's disease [4, 11, 15].

Other names

ALDH-E2ALDHIALDMAldehyde dehydrogenase 2 family memberMitochondrial aldehyde dehydrogenase

ALDH2 is targeted through two primary pharmacological approaches: inhibition and activation. Inhibitors like disulfiram block the enzyme's ability to metabolize acetaldehyde, leading to its toxic accumulation and inducing aversive symptoms (flushing, nausea) to deter alcohol consumption [13, 17]. Conversely, activators like Alda-1 enhance the enzyme's catalytic efficiency, particularly in individuals with the ALDH2*2 variant, to accelerate the detoxification of reactive aldehydes and mitigate oxidative damage in cardiovascular and neurodegenerative diseases [2, 4, 14]. Additionally, ALDH2 acts as a bioactivating enzyme for nitroglycerin, converting it into nitric oxide [7, 16].