Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Shan Zhang, Boris Reljić, 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 and Lena Ho ()
Additional contact information
Shan Zhang: Duke-NUS Medical School
Boris Reljić: University of Melbourne
Chao Liang: Duke-NUS Medical School
Baptiste Kerouanton: Duke-NUS Medical School
Joel Celio Francisco: Duke-NUS Medical School
Jih Hou Peh: Duke-NUS Medical School
Camille Mary: Geneva University
Narendra Suhas Jagannathan: Centre for Computational Biology, Duke-NUS Graduate Medical School Singapore
Volodimir Olexiouk: Ghent University
Claire Tang: Duke-NUS Medical School
Gio Fidelito: Duke-NUS Medical School
Srikanth Nama: Institute of Medical Biology, A*STAR
Ruey-Kuang Cheng: Nanyang Technological University
Caroline Lei Wee: Institute of Molecular and Cell Biology, A*STAR
Loo Chien Wang: Institute of Molecular and Cell Biology, A*STAR
Paula Duek Roggli: SIB-Swiss Institute of Bioinformatics
Prabha Sampath: Skin Research Institute of Singapore, A*STAR
Lydie Lane: Geneva University
Enrico Petretto: Centre for Computational Biology, Duke-NUS Graduate Medical School Singapore
Radoslaw M. Sobota: Institute of Molecular and Cell Biology, A*STAR
Suresh Jesuthasan: Nanyang Technological University
Lisa Tucker-Kellogg: Duke-NUS Medical School
Bruno Reversade: Institute of Medical Biology, A*STAR
Gerben Menschaert: Ghent University
Lei Sun: Duke-NUS Medical School
David A. Stroud: University of Melbourne
Lena Ho: Duke-NUS Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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 AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

Date: 2020
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DOI: 10.1038/s41467-020-14999-2

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