Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice.
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.
Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Tara R
TR
Richman
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
Henrik
H
Spåhr
Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Judith A
JA
Ermer
Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
Stefan M K
SM
Davies
School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Western Australia 6009, Australia.
Helena M
HM
Viola
Experimental and Regenerative Neuroscience, School of Animal Biology, University of Western Australia Crawley, Western Australia 6009, Australia.
Kristyn A
KA
Bates
School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia.
John
J
Papadimitriou
School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Western Australia 6009, Australia.|Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
Livia C
LC
Hool
Experimental and Regenerative Neuroscience, School of Animal Biology, University of Western Australia Crawley, Western Australia 6009, Australia.
Jennifer
J
Rodger
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.|Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
Nils-Göran
NG
Larsson
Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.|School of Chemistry and Biochemistry, University of Western Australia, Crawley, Western Australia 6009, Australia.
Oliver
O
Rackham
Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.|School of Chemistry and Biochemistry, University of Western Australia, Crawley, Western Australia 6009, Australia.
Aleksandra
A
Filipovska
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D014176:Protein Biosynthesis; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism; D000077278:RNA, Mitochondrial; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D008840:Microfilament Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; D011994:Recombinant Proteins; C029305:mitochondrial messenger RNA; C072061:coronin proteins