Mitochondrial mutations, human diseases, and drug-resistant pathogens

Mutations in mitochondrial genes are associated with a growing number of diseases in human beings. More than 100 point mutations have been reported.1 These genetic lesions are located in genes coding for subunits of the respiratory complexes-complex I, complex III, cytochrome oxidase, and ATPase-and for the mitochondrial translation apparatus: rRNAs and tRNAs.

To characterise the effects of these disease-related mutations, we use yeast as a model system. Since yeast is amenable to mitochondrial transformation, designed mutations can be introduced in its mitochondrial genome. Yeast mutants harbouring the model human mutations can then be used to characterise the deleterious effect of these mutations and to explore ways of restoring the respiratory function impaired by these genetic lesions (figure 1).

Inhibitors of the respiratory-chain complex bc1 are widely used in medicine and in agriculture to control pathogens. Mutations in the mitochondrially-encoded cytochrome b gene have been reported in human and plant parasites that are resistant to treatment by these inhibitors.

To provide easy-to-use models for study of acquired resistance, we introduce inhibitor-resistant mutations into yeast cytochrome b. We then use the yeast strains with modified bc1 complex to characterise the effects of the mutations on respiratory function and cross-resistance to other drugs (figure 2).