Defects in the components or regulatory factors of mitochondrial complexes can cause diseases with wide-ranging phenotypes. Although mitochondrial diseases associated with complex I (CI) dysfunction are common, CI remains the least well-defined complex of the electron transport chain owing to its large size and complexity. Ricardo Escalante and colleagues recently identified the mitochondrial protein MidA, which is conserved between Dictyostelium and humans. On page 1674, they report additional findings suggesting that this protein regulates CI stability and/or function. Dictyostelium midA− cells show a 50% decrease in CI activity, and knockdown of MidA expression in HEK293T cells decreases the amount of assembled CI. In addition, a yeast-two-hybrid assay shows that MidA interacts with the CI subunit NDUFS2. Bioinformatics approaches predict that MidA acts as a methyltransferase and identify the glycine residue(s) that are important for this activity. Furthermore, site-directed mutagenesis experiments confirm the importance of the putative methyltransferase domain for MidA function. Therefore, methylation of CI seems to be important for its function. In addition, the phenotype of Dictyostelium midA− cells – which display characteristics including defects in development and phototaxis – emphasises the complex pathology underlying CI-related mitochondrial diseases.
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