Polymorphisms in mitochondrial genes encoding complex I subunits are maternal factors of voluntary alcohol consumption in the rat

Objective Alcohol is detoxified in the liver by oxidizing enzymes that require nicotinamide adenine dinucleotide (NAD(+)) such that, in the rat, the availability of NAD(+) contributes to control voluntary ethanol intake. The UChA and UChB lines of Wistar rats drink low and high amounts of ethanol respectively and differ in the capacity of their mitochondria to oxidize NADH into NAD(+). This function resides in complex I of the respiratory chain and its variation is linked to genes transmitted through the maternal line. The aim of this study was to identify the genetic basis for the difference in the reoxidation of NADH in these nondrinker (UChA) and drinker (UChB) rats. Methods Seven mitochondrial genes and two chromosome X genes encoding complex I subunits from rats of both lineages were amplified from liver DNA and sequenced. Results The UChA and UChB rat lines differ in their Nd2, Nd4, Nd5 and Nd6 mitochondrial genes and in the encoded proteins. Most noteworthy are ND2 and ND4 whose amino acid variations lead to changes in three-dimensional structure models. The ND2 proteins also differ in the number of predicted transmembrane domains. The Nd1 and Nd3 genes have silent substitutions, whereas Nd4L and the exonic sequences of the nuclear genes Ndufa1 and Ndufb11 show no differences between the UChA and UChB lines. Conclusion Amino acid variations in four complex I subunits encoded in the mitochondrial genome may contribute to explain the differences between UChA and UChB rats in their capacity to reoxidize NADH and in their alcohol intake, suggesting that mitochondrial genes may constitute maternal factors of alcoholism. Pharmacogenetics and Genomics 19:528-537 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.