Defects in mitochondrial translation are among the most common causes of mitochondrial disease1, but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5′ UTRs and mediate translation2. As mammalian mitochondrial mRNAs do not have significant 5′ UTRs3, alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs4, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
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We acknowledge the contribution of the individuals who cared for the study subjects and the technical assistance of I. Kaus, S. Mueller-Ziermann and A. Zimmermann. We thank T. Johns for help with immunocytochemistry and the cell culture. This work was supported in part by a grant from the Canadian Institutes of Health Research to E.A.S. E.A.S. is an International Scholar of the Howard Hughes Medical Institute. R.H. is supported by the Deutsche Forschungsgemeinschaft HO 2505/2-1.
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