The cytochrome oxidase defect in ISC‐depleted yeast is caused by impaired iron–sulfur cluster maturation of the mitoribosome assembly factor Rsm22

Mitochondria contain the bacteria‐inherited iron–sulfur cluster assembly (ISC) machinery to generate cellular iron–sulfur (Fe/S) proteins. Mutations in human ISC genes cause severe disorders with a broad clinical spectrum and are associated with strong defects in mitochondrial Fe/S proteins, including respiratory complexes I–III. For unknown reasons, complex IV (aka cytochrome c oxidase), a non‐Fe/S, heme‐containing enzyme, is severely affected. Using yeast as a model, we show that depletion of Rsm22, the counterpart of the human mitoribosome assembly factor METTL17, phenocopies the defects observed upon impairing late‐acting ISC proteins, that is, diminished activities of mitoribosomal translation and respiratory complexes III and IV. Rsm22 binds Fe/S clusters in vivo , thereby satisfactorily explaining the defect of respiratory complex IV in ISC‐deficient cells, because this complex contains three mitochondrial DNA‐encoded subunits. Impact statement Defects in mitochondrial Fe/S protein biogenesis also impact respiratory complex IV (COX), even though it lacks Fe/S clusters. Here, we show that the mitoribosome assembly factor Rsm22 binds Fe/S clusters in vivo. Rsm22 maturation defects impair mitoribosomal protein translation including COX subunits, explaining the COX defects in Fe/S cluster‐deficient cells.