Maternal inheritance, mitochondrial complex I and alcohol consumption: differences between nondrinker (UChA) and drinker (UChB) rats in three mitochondrial genes
Mitochondrial complex I, which oxidizes mitochondrial NADH to NAD+, has a lower oxidation capacity in low drinker UChA rats than in UChB drinker rats. Lower availability of NAD+ in UChA rats contributes to higher acetaldehyde levels since aldehyde dehydrogenase requires mitochondrial NAD+ as a cofactor to metabolize acetaldehyde.
Four genes of maternal inheritance coding for subunits of mitochondrial complex I were studied in search for differences between the UChA and UChB rat lines that might explain their differences in NADH oxidation capacity. Genes Nd1, Nd2 and Nd4 are in the mitochondrial genome while NdufaI is found in the X chromosome. Genes were amplified from total DNA by PCR and sequenced directly. Five rats of each lineage were analysed.
The Nd1, Nd2 and Nd4 genes of the UChA and UChB lines vary at 7 positions each. The Nd2 and Nd4 genes code for proteins that differ between lines. There are 5 variations in the ND2 proteins: positions 150 (Ser/Asn), 217 (Thr/Ile), 265 (Thr/Ala) and 304 (Met/Thr) (UChA/UChB) and an additional histidine in UChA after aa 317. The ND4 proteins have two polymorphic positions: 23 (Thr/Ile) and 419 (Pro/Leu) (UChA/UChB). The deduced sequences for the UChA ND2 and ND4 proteins have not been described previously. The Nd1 genes, while different, code for identical proteins. The three exons for NdufaI that encode the MWFE protein are identical in both lines.
Overall, the UChA and UChB rat lines differ in their ND2 proteins (4 aa and 1 insertion) and in their ND4 proteins (2 aa) but code for identical ND1 and MWFE proteins. Some of the amino acid variations may explain the differences between lines in their capacity to oxidize NADH by complex I and hence in their alcohol intake. Additionally, the nucleotide variations found in genes Nd1, Nd2 and Nd4 may affect the translation of mitochondrial genes or the stability of the transcripts, impinging on the relative abundance of complex I components and its activity.
FONDECYT 1050480