Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Shan Zhang; Boris Reljic; Chao Liang; Baptiste Kerouanton; Joel Celio Francisco; Jih Hou Peh; Camille Mary; Narendra Suhas Jagannathan; Volodimir Olexiouk; Claire Tang; Gio Fidelito; Srikanth Nama; Ruey-Kuang Cheng; Caroline Lei Wee; Loo Chien Wang; Paula Duek Roggli; Prabha Sampath; Lydie Lane; Enrico Petretto; Radoslaw M Sobota; Suresh Jesuthasan; Lisa Tucker-Kellogg; Bruno Reversade; Gerben Menschaert; Lei Sun; David A Stroud; Lena Ho

Journal article

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Shan Zhang, Boris Reljic, Chao Liang, Baptiste Kerouanton, Joel Celio Francisco, Jih Hou Peh, Camille Mary, Narendra Suhas Jagannathan, Volodimir Olexiouk, Claire Tang, Gio Fidelito, Srikanth Nama, Ruey-Kuang Cheng, Caroline Lei Wee, Loo Chien Wang, Paula Duek Roggli, Prabha Sampath, Lydie Lane, Enrico Petretto, Radoslaw M Sobota Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2020

DOI: 10.1038/s41467-020-14999-2

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Abstract

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AM..

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University of Melbourne Researchers

David Stroud Author Biochemistry and Pharmacology

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Grants

Awarded by Australian National Health & Medical Research Council (NHMRC)

Awarded by National Research Foundation of Singapore

Awarded by Howard Hughes Medical Institute International Research Scholar Program

Funding Acknowledgements

We thank the IMCB Aquatics facility, the IMU Imaging facility and the AMPL histopathology unit at A*STAR for providing technical support; JP Kovalik and Ching Jianhong from the Duke-NUS metabolomics facility for metabolomic analysis including assay development; Hu Zhen, Kor Chia Yee, and Jes Kwek Hui Min for their technical support; Aida Moreno Moral and Cheryl Lee for their inputs on bioinformatics analyses; Brijesh Kumar Singh for his assistance with the Agilent Seahorse platform; Sudipto Roy from IMCB for help with zebrafish muscle analyses. We thank Pui Mun Wong and Serene Chng for their assistance in generating zebrafish crispr knockout, and Wei Leong Chew from Genome Institute of Singapore for assistance with AAV generation. We thank Radiance Lim for her assistance in AAV injection. We thank the Bio21 Melbourne Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation, training, and technical support. D.A.S. is supported by Australian National Health & Medical Research Council (NHMRC) grants GNT1140851 and GNT1140906. L.L. and C.M. are supported by Fondation Ernst & Lucie Schmidheiny. This work is funded by fellowships NRF-NRFF2017-05 (National Research Foundation of Singapore) and HHMI-IRSP55008732 (Howard Hughes Medical Institute International Research Scholar Program) awarded to L.H.