Combined Effects of Aldehyde Dehydrogenase Variants and Maternal Mitochondrial Genes on Alcohol Consumption

Two lines of rats bred to differ in their voluntary alcohol consumption—the alcohol-abstaining UChA rats and the alcohol-drinking UChB rats—differ in how effectively toxic acetaldehyde is removed during alcohol metabolism. UChB animals carry efficient variants of the aldehyde dehydrogenase 2 (ALDH2) genes and have active mitochondria, resulting in fast removal of acetaldehyde. UChA animals, in contrast, carry less efficient ALDH2 variants and less active mitochondria, which result in transient elevations of acetaldehyde levels after alcohol ingestion. Cross-breeding studies have demonstrated that the presence of active mitochondria inherited from UChB females can fully abolish the reduction of alcohol consumption associated with the presence of less efficient ALDH2 variants—a phenomenon known as epistasis. These and other findings suggest that mitochondrial activity during alcohol metabolism should be considered a new modulator of alcohol consumption not only in rats but also in other species, including humans.