ALDH2 rs671 variant enhances platelet activation and thrombosis by disrupting mitochondrial complex I assembly

Aldehyde dehydrogenase 2 (ALDH2) is a critical mitochondrial enzyme responsible for aldehyde detoxification and maintenance of redox homeostasis. The rs671 variant, a prevalent loss-of-function mutation in East Asian populations (30–50% carrier frequency), diminishes ALDH2 enzymatic activity by 60–90% and is associated with elevated thrombotic risk. Although platelet activation is known to play a central role in thrombosis formation, the specific contribution of ALDH2 to this process has not been fully elucidated. This study was designed to investigate the functional role of ALDH2 in platelet activation and thrombus formation.

Platelet activation and thrombus formation were assessed in wild-type (WT), systemic Aldh2-knockout (Aldh2^−/−), and systemic Aldh2^E487K/E487K-knockin mice, as well as patients with coronary artery disease (CAD) and healthy volunteers. Mechanistic studies were performed using immunoprecipitation, mass spectrometry, and RNA sequencing. Nicotinamide adenine dinucleotide (NAD⁺) supplementation was evaluated for its potential to mitigate the effects of ALDH2 variant. Patients with CAD carrying the ALDH2 rs671 variant exhibited enhanced platelet reactivity to collagen compared with those without the variant. Collagen-induced platelet aggregation, granule release, and integrin αIIbβ3 activation were significantly enhanced in Aldh2^−/− mice compared with WT mice. Mechanistically, ALDH2 deficiency disrupted mitochondrial complex I assembly and function. This increased reactive oxygen species production via the collagen/glycoprotein VI (GPVI)/NAD phosphate oxidase 1 (NOX1) pathway and enhanced platelet reactivity. Similar results were observed in Aldh2^E487K/E487K-knockin mice. NAD⁺ supplementation effectively counteracted ALDH2 variant-induced platelet hyperreactivity and thrombosis in both mice and human subjects.

The ALDH2 rs671 variant enhances collagen-induced platelet activation and thrombosis by impairing mitochondrial complex I assembly and function. NAD⁺ supplementation offers a promising strategy to mitigate thrombotic risk in individuals carrying this variant.