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Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats
Author(s) -
Quintanilla María Elena,
Tampier Lutske,
Valle-Prieto Araceli,
Sapag Amalia,
Israel Yedy
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2172com
Subject(s) - aldehyde dehydrogenase , aldh2 , acetaldehyde , ethanol , mitochondrion , offspring , ethanol metabolism , alcohol dehydrogenase , cyp2e1 , biology , nad+ kinase , alcohol , allele , gene , biochemistry , oxidoreductase , medicine , enzyme , endocrinology , genetics , cytochrome p450 , pregnancy
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 F 2 offspring. Ninety‐seven percent of Wistar‐derived rats selectively bred for their voluntary low‐alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh2 2 that encodes an en‐ zyme with a low affinity for NAD + , whereas rats bred for high‐alcohol consumption do not present the Aldh2 2 al‐ lele. This enzyme is inserted into mitochondria, where NADH‐ubiquinone oxidoreductase (complex I) regener‐ ates NAD + . The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investi‐ gated. Homozygous Aldh2 2 /Aldh2 2 rats derived from a line of high‐drinker F 0 females (and low‐drinker F 0 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 F 0 females (and high‐drinker F 0 males) (1.8±0.4 g•kg ‐1 •day ‐1 ). Mitochondria of F 2 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‐con‐ suming 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 pheno‐ typic 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. Com‐ plex I regulates mutant mitochondrial aldehyde dehydro‐ genase activity and voluntary ethanol consumption in rats. FASEBJ. 19, 36‐42 (2005)