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Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

María Elena Quintanilla, Lutske Tampier, Araceli Valle-Prieto^*, Amalia Sapag^* and Yedy Israel^*,,1

Program of Molecular and Clinical Pharmacology, Faculty of Medicine;
^* Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences and Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, University of Chile, Santiago, Chile; and
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

¹Correspondence: Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry and Millennium Institute-CBB, University of Chile. Olivos 1007, Santiago, RM 838-0492 Chile. E-mail: Yedy.Israel{at}jefferson.edu

Animals selectively bred for a desirable trait retain wanted genes but exclude genes that may counteract the expression of the former. The possible interactions between selected and excluded genes cannot be readily studied in transgenic or knockout animals but may be addressed by crossing animals bred for opposite traits and studying the F₂ offspring. Ninety-seven percent of Wistar-derived rats selectively bred for their voluntary low-alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh2² that encodes an enzyme with a low affinity for NAD⁺, whereas rats bred for high-alcohol consumption do not present the Aldh2² allele. This enzyme is inserted into mitochondria, where NADH-ubiquinone oxidoreductase (complex I) regenerates NAD⁺. The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investigated. Homozygous Aldh2²/Aldh2² rats derived from a line of high-drinker F₀ females (and low-drinker F₀ males) showed a markedly higher ethanol consumption (3.9±0.5 g·kg^–1·day^–1) than homozygous animals derived from a line of low-drinker F₀ females (and high-drinker F₀ males) (1.8±0.4 g·kg^–1·day^–1). Mitochondria of F₂ rats derived from high alcohol-consuming females were more active in oxidizing substrates that generate NADH for complex I than were mitochondria derived from low alcohol-consuming females, leading in the former to higher rates of acetaldehyde metabolism and to a reduced aversion to ethanol. This is the first demonstration that maternally derived genes can either allow or counteract the phenotypic expression of a mutated gene in the context of alcohol abuse or alcoholism.—Quintanilla, M. E., Tampier, L., Valle-Prieto, A., Sapag, A., Israel, Y. Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats.

Key Words: alcoholism • penetrance • mitochondria • mtDNA • polymorphism