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Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly.

  • Zhang S Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Reljić B Department of Biochemistry and Molecular Biology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
  • Liang C Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Kerouanton B Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Francisco JC Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Peh JH Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Mary C SIB-Swiss Institute of Bioinformatics and Department of Microbiology and Molecular Medicine, Faculty of Medicine, Geneva University, Geneva, Switzerland.
  • Jagannathan NS Centre for Computational Biology, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
  • Olexiouk V Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
  • Tang C Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Fidelito G Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Nama S Institute of Medical Biology, A*STAR, Singapore, Singapore.
  • Cheng RK Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • Wee CL Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • Wang LC Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • Duek Roggli P SIB-Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Sampath P Skin Research Institute of Singapore, A*STAR, Singapore, Singapore.
  • Lane L SIB-Swiss Institute of Bioinformatics and Department of Microbiology and Molecular Medicine, Faculty of Medicine, Geneva University, Geneva, Switzerland.
  • Petretto E Centre for Computational Biology, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
  • Sobota RM Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
  • Jesuthasan S Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • Tucker-Kellogg L Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore.
  • Reversade B Institute of Medical Biology, A*STAR, Singapore, Singapore.
  • Menschaert G Biobix, Lab of Bioinformatics and Computational Genomics, Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
  • Sun L Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore.
  • Stroud DA Department of Biochemistry and Molecular Biology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, Australia.
  • Ho L Cardiovascular Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore. lena@ho-lab.org.
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  • 2020-03-13
Published in:
  • Nature communications. - 2020
Acidosis, Lactic
Animals
Animals, Genetically Modified
Disease Models, Animal
Electron Transport Complex III
Female
Gene Knockdown Techniques
Growth Disorders
Humans
Male
Metabolomics
Mitochondria
Mitochondrial Proteins
Models, Animal
Models, Biological
Open Reading Frames
Oxidative Phosphorylation
Peptides
Proteomics
Zebrafish
Zebrafish Proteins
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/229822
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