Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Title:
Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly
Other Titles:
Nature Communications
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Publication Date:
11 March 2020
Citation:
Zhang, S., Reljić, B., Liang, C. et al. Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Nat Commun 11, 1312 (2020). https://doi.org/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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
D.A.S. is supported by Australian National Health & Medical Research Council (NHMRC) grants GNT1140851 and GNT1140906. L.L. and C.M. are supported by Fondation Ernst & Lucie Schmidheiny. This work is funded by fellowships NRF-NRFF2017-05 (National Research Foundation of Singapore) and HHMI-IRSP55008732 (Howard Hughes Medical Institute International Research Scholar Program) awarded to L.H.
Description:
ISSN:
2041-1723
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