ZFIN ID: ZDB-PUB-200403-39
Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Zhang, S., Reljić, B., Liang, C., Kerouanton, B., Francisco, J.C., Peh, J.H., Mary, C., Jagannathan, N.S., Olexiouk, V., Tang, C., Fidelito, G., Nama, S., Cheng, R.K., Wee, C.L., Wang, L.C., Duek Roggli, P., Sampath, P., Lane, L., Petretto, E., Sobota, R.M., Jesuthasan, S., Tucker-Kellogg, L., Reversade, B., Menschaert, G., Sun, L., Stroud, D.A., Ho, L.
Date: 2020
Source: Nature communications   11: 1312 (Journal)
Registered Authors: Ho, Lena, Jesuthasan, Suresh, Lane, Lydie, Mary, Camille, REVERSADE, Bruno
Keywords: none
MeSH Terms:
  • Acidosis, Lactic/genetics
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Electron Transport Complex III/metabolism*
  • Female
  • Gene Knockdown Techniques
  • Growth Disorders/genetics
  • Humans
  • Male
  • Metabolomics
  • Mitochondria/metabolism*
  • Models, Animal
  • Models, Biological
  • Open Reading Frames/genetics
  • Oxidative Phosphorylation*
  • Peptides/genetics
  • Peptides/metabolism*
  • Proteomics
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 32161263 Full text @ Nat. Commun.
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.