TY - JOUR T1 - BRAWNIN: A sORF-encoded Peptide Essential for Vertebrate Mitochondrial Complex III Assembly JF - bioRxiv DO - 10.1101/2020.01.31.926402 SP - 2020.01.31.926402 AU - Shan Zhang AU - Chao Liang AU - Camille Mary AU - Baptiste Kerouanton AU - Joel Francisco AU - Narendra Suhas Jagannathan AU - Volodimir Olexiouk AU - Jih Hou Peh AU - Claire Tang AU - Gio Fidelito AU - Srikanth Nama AU - Ruey-Kuang Cheng AU - Caroline Lei Wee AU - Loo Chien Wang AU - Paula Duek Roggli AU - Prabha Sampath AU - Lydie Lane AU - Enrico Petretto AU - Radoslaw Sobota AU - Suresh Jesuthasan AU - Lei Sun AU - Lisa Tucker-Kellogg AU - Bruno Reversade AU - Gerben Menschaert AU - David A. Stroud AU - Lena Ho Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/01/2020.01.31.926402.abstract N2 - The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution1,2. Here, we show that the mitochondria proteome is enriched for proteins smaller than 100 a.a. (defined as SEPs). Using a mitochondrial prediction and validation pipeline for small open-reading-frame (sORF)-encoded peptides (SEPs), we report the discovery of 16 endogenous mitochondrial SEPs (mito-SEPs) associated with oxidative phosphorylation (OXPHOS). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN (BR), a 71 amino acid peptide encoded by the C12orf73 gene, is essential for respiratory chain complex III (CIII) assembly. In human cells, BR is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In vivo, BR is enriched in muscle tissues and its maternal zygotic deletion in zebrafish causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BR is essential for oxidative phosphorylation across vertebrate species. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism. ER -