Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

  • Nat Commun. 2020 Mar 11;11(1):1312. doi: 10.1038/s41467-020-14999-2.
Shan Zhang  1 ,  Boris Reljić  #  2 ,  Chao Liang  #  1 ,  Baptiste Kerouanton  #  1 ,  Joel Celio Francisco  3 ,  Jih Hou Peh  1 ,  Camille Mary  4 ,  Narendra Suhas Jagannathan  5 ,  Volodimir Olexiouk  6 ,  Claire Tang  1 ,  Gio Fidelito  1 ,  Srikanth Nama  7 ,  Ruey-Kuang Cheng  8 ,  Caroline Lei Wee  9 ,  Loo Chien Wang  9 ,  Paula Duek Roggli  10 ,  Prabha Sampath  11 ,  Lydie Lane  4 ,  Enrico Petretto  5 ,  Radoslaw M Sobota  9 ,  Suresh Jesuthasan  8  9 ,  Lisa Tucker-Kellogg  3  5 ,  Bruno Reversade  7  9 ,  Gerben Menschaert  6 ,  Lei Sun  1 ,  David A Stroud  2 ,  Lena Ho  12  13
Affiliations
  • 1. Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • 2. Department of Biochemistry and Molecular Biology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
  • 3. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • 4. SIB-Swiss Institute of Bioinformatics and Department of Microbiology and Molecular Medicine, Faculty of Medicine, Geneva University, Geneva, Switzerland.
  • 5. Centre for Computational Biology, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
  • 6. Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
  • 7. Institute of Medical Biology, A*STAR, Singapore, Singapore.
  • 8. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 9. Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • 10. SIB-Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • 11. Skin Research Institute of Singapore, A*STAR, Singapore, Singapore.
  • 12. Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore. [email protected].
  • 13. Institute of Medical Biology, A*STAR, Singapore, Singapore. [email protected].
  • # Contributed equally.
PMID: 32161263 DOI: 10.1038/s41467-020-14999-2
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.