| ALDH2 is a mitochondrial aldehyde dehydrogenase that oxidizes reactive aldehydes, including ethanol‑derived acetaldehyde and lipid peroxidation products, to their corresponding acids using NAD⁺ as cofactor, placing it at a key junction between alcohol metabolism, oxidative stress control, and cellular redox balance. The enzyme assembles as a homotetramer, with each subunit contributing a conserved aldehyde dehydrogenase fold that contains a catalytic cysteine, a general base glutamate, and a Rossmann‑like NAD⁺‑binding domain, and this quaternary structure stabilizes the active sites and supports efficient substrate turnover under mitochondrial conditions. During catalysis, the catalytic cysteine performs nucleophilic attack on the aldehyde to form a thiohemiacetal intermediate, which then undergoes hydride transfer to NAD⁺ to generate NADH, followed by hydrolysis of the thioester and release of the carboxylic acid product, so ALDH2 activity directly links aldehyde detoxification to mitochondrial NADH production and downstream respiratory chain function. Within the mitochondrial matrix, ALDH2 processes acetaldehyde produced by cytosolic and mitochondrial alcohol dehydrogenases and clears endogenous aldehydes such as 4‑hydroxy‑2‑nonenal and other lipid‑derived adduct‑forming species generated during oxidative stress, limiting covalent modification of proteins, nucleic acids, and membrane lipids. Reduced ALDH2 function allows accumulation of reactive aldehydes that impair mitochondrial proteins, activate stress‑responsive signaling pathways, alter calcium handling, and shift apoptotic thresholds, whereas preserved activity supports mitochondrial integrity, ATP generation, and resistance to oxidative insults in high‑demand tissues such as myocardium and brain. A common missense polymorphism, ALDH2*2, introduces a Glu‑to‑Lys substitution that strongly decreases catalytic efficiency by destabilizing cofactor binding and active‑site geometry, and carriers have reduced acetaldehyde clearance, characteristic flushing after alcohol intake, and increased exposure to both acetaldehyde and lipid‑derived aldehydes. This low‑activity variant and related genotypes are associated with higher risk of upper aerodigestive tract and esophageal cancers in drinkers, where persistent aldehyde exposure promotes DNA adduct formation, mutagenesis, and chromosomal instability, although reduced alcohol consumption in some carriers can modify the overall risk profile. In tumor settings, decreased ALDH2 expression favors aldehyde‑driven genomic damage, while elevated ALDH2 expression provides enhanced detoxification capacity that supports proliferation and survival under oxidative and metabolic stress, so ALDH2 levels and activity influence tumor initiation, progression, and responses to metabolic or genotoxic therapies in a context‑dependent manner. |
