The clinically relevant triple mutation in the mtND1 gene inactivates Escherichia coli complex I.

NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in cellular energy metabolism. Complex I deficiencies are the most common cause of mitochondrial dysfunction. Patients suffering from a variety of neurodegenerative diseases carry numerous mutations in the mitochondrially encoded subunits of the complex. The biochemical consequences of these mutations are largely unknown because these genes are difficult to access experimentally. Here, we use Escherichia coli as a model system to characterize the effect of a 7 bps inversion in mtND1 (m.3902-3908inv7) that results in a triple mutation. The triple mutant grew poorly but contained a normal amount of the stably assembled variant. The variant showed no enzymatic activity, which might contribute to the deleterious effect of the mutation in humans.