Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice

• Published in: Nature communications 2016-06, Vol.7 (1), p.11884-11884, Article 11884
• Main Authors: Richman, Tara R., Spåhr, Henrik, Ermer, Judith A., Davies, Stefan M. K., Viola, Helena M., Bates, Kristyn A., Papadimitriou, John, Hool, Livia C., Rodger, Jennifer, Larsson, Nils-Göran, Rackham, Oliver, Filipovska, Aleksandra
• Format: Article
• Language: English
• Subjects: 631/337/574/1789; 631/45/612/1230; 64/60; 692/699; Amino Acid Sequence; Animals; Binding Sites; Biochemistry; Biology; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cloning, Molecular; Crystallography, X-Ray; Cytochrome; Dystonia; Escherichia coli - genetics; Escherichia coli - metabolism; Genes; Genomes; Heart; Humanities and Social Sciences; Male; Medical research; Medicin och hälsovetenskap; Metabolism; Mice; Mice, Knockout; Microfilament Proteins - chemistry; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Models, Molecular; multidisciplinary; Mutation; Protein Binding; Protein Biosynthesis; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Ribonucleic acid; RNA; RNA, Messenger - chemistry; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Sequence Alignment; Sequence Homology, Amino Acid; Visual impairment
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11884

The recognition and translation of mammalian mitochondrial mRNAs are poorly understood. To gain further insights into these processes in vivo, we characterized mice with a missense mutation that causes loss of the translational activator of cytochrome oxidase subunit I (TACO1). We report that TACO1 is not required for embryonic survival, although the mutant mice have substantially reduced COXI protein, causing an isolated complex IV deficiency. We show that TACO1 specifically binds the mt-Co1 mRNA and is required for translation of COXI through its association with the mitochondrial ribosome. We determined the atomic structure of TACO1, revealing three domains in the shape of a hook with a tunnel between domains 1 and 3. Mutations in the positively charged domain 1 reduce RNA binding by TACO1. The Taco1 mutant mice develop a late-onset visual impairment, motor dysfunction and cardiac hypertrophy and thus provide a useful model for future treatment trials for mitochondrial disease. Mutations in the translational activator of cytochrome c oxidase subunit I (TACO1) causes cytochrome c oxidase deficiency and Leigh Syndrome in patients. Here, the authors characterize mice with a mutation that causes lack of TACO1 expression, identifying a mouse model that could be useful for preclinical trials.