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Sci Adv. 2019 Dec 20;5(12):eaay2118. doi: 10.1126/sciadv.aay2118. eCollection 2019 Dec.

Fidelity of translation initiation is required for coordinated respiratory complex assembly.

Author information

1
Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
2
Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
3
Centre for Microscopy, Characterisation and Analysis and School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia 6009, Australia.
4
School of Human Sciences (Physiology), The University of Western Australia, Crawley, Western Australia 6009, Australia.
5
Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
6
School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia 6102, Australia.
7
Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia 6102, Australia.
8
School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia 6009, Australia.

Abstract

Mammalian mitochondrial ribosomes are unique molecular machines that translate 11 leaderless mRNAs; however, it is not clear how mitoribosomes initiate translation, since mitochondrial mRNAs lack untranslated regions. Mitochondrial translation initiation shares similarities with prokaryotes, such as the formation of a ternary complex of fMet-tRNAMet, mRNA and the 28S subunit, but differs in the requirements for initiation factors. Mitochondria have two initiation factors: MTIF2, which closes the decoding center and stabilizes the binding of the fMet-tRNAMet to the leaderless mRNAs, and MTIF3, whose role is not clear. We show that MTIF3 is essential for survival and that heart- and skeletal muscle-specific loss of MTIF3 causes cardiomyopathy. We identify increased but uncoordinated mitochondrial protein synthesis in mice lacking MTIF3, resulting in loss of specific respiratory complexes. Ribosome profiling shows that MTIF3 is required for recognition and regulation of translation initiation of mitochondrial mRNAs and for coordinated assembly of OXPHOS complexes in vivo.

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