Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Shan Zhang; Boris Reljić; Chao Liang; Baptiste Kerouanton; Joel Celio Francisco; Jih Hou Peh; Camille Mary; Narendra Suhas Jagannathan; Volodimir Olexiouk; Claire Tang; Gio Fidelito; Srikanth Nama; Ruey Kuang Cheng; Caroline Lei Wee; Loo Chien Wang; Paula Duek Roggli; Prabha Sampath; Lydie Lane; Enrico Petretto; Radoslaw M. Sobota; Suresh Jesuthasan; Lisa Tucker-Kellogg; Bruno Reversade; Gerben Menschaert; Lei Sun; David A. Stroud; Lena Ho

doi:10.1038/s41467-020-14999-2

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Shan Zhang, Boris Reljić, Chao Liang, Baptiste Kerouanton, Joel Celio Francisco, Jih Hou Peh, Camille Mary, Narendra Suhas Jagannathan, Volodimir Olexiouk, Claire Tang, Gio Fidelito, Srikanth Nama, Ruey Kuang Cheng, Caroline Lei Wee, Loo Chien Wang, Paula Duek Roggli, Prabha Sampath, Lydie Lane, Enrico Petretto, Radoslaw M. SobotaSuresh Jesuthasan, Lisa Tucker-Kellogg, Bruno Reversade, Gerben Menschaert, Lei Sun, David A. Stroud, Lena Ho

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

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.

Original language	English (US)
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14999-2
State	Published - Dec 1 2020
Externally published	Yes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
General Chemistry
General Physics and Astronomy

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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., ... Ho, L. (2020). Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-14999-2

@article{2b536024a0ed48d689f359cd33bee256,

title = "Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly",

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.",

author = "Shan Zhang and Boris Relji{\'c} and Chao Liang and Baptiste Kerouanton and Francisco, {Joel Celio} and Peh, {Jih Hou} and Camille Mary and Jagannathan, {Narendra Suhas} and Volodimir Olexiouk and Claire Tang and Gio Fidelito and Srikanth Nama and Cheng, {Ruey Kuang} and Wee, {Caroline Lei} and Wang, {Loo Chien} and {Duek Roggli}, Paula and Prabha Sampath and Lydie Lane and Enrico Petretto and Sobota, {Radoslaw M.} and Suresh Jesuthasan and Lisa Tucker-Kellogg and Bruno Reversade and Gerben Menschaert and Lei Sun and Stroud, {David A.} and Lena Ho",

note = "Generated from Scopus record by KAUST IRTS on 2023-02-15",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14999-2",

language = "English (US)",

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Zhang, S, Reljić, B, Liang, C, Kerouanton, B, Francisco, JC, Peh, JH, Mary, C, Jagannathan, NS, Olexiouk, V, Tang, C, Fidelito, G, Nama, S, Cheng, RK, Wee, CL, Wang, LC, Duek Roggli, P, Sampath, P, Lane, L, Petretto, E, Sobota, RM, Jesuthasan, S, Tucker-Kellogg, L, Reversade, B, Menschaert, G, Sun, L, Stroud, DA & Ho, L 2020, 'Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly', Nature Communications, vol. 11, no. 1. https://doi.org/10.1038/s41467-020-14999-2

TY - JOUR

T1 - Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

AU - Zhang, Shan

AU - Reljić, Boris

AU - Liang, Chao

AU - Kerouanton, Baptiste

AU - Francisco, Joel Celio

AU - Peh, Jih Hou

AU - Mary, Camille

AU - Jagannathan, Narendra Suhas

AU - Olexiouk, Volodimir

AU - Tang, Claire

AU - Fidelito, Gio

AU - Nama, Srikanth

AU - Cheng, Ruey Kuang

AU - Wee, Caroline Lei

AU - Wang, Loo Chien

AU - Duek Roggli, Paula

AU - Sampath, Prabha

AU - Lane, Lydie

AU - Petretto, Enrico

AU - Sobota, Radoslaw M.

AU - Jesuthasan, Suresh

AU - Tucker-Kellogg, Lisa

AU - Reversade, Bruno

AU - Menschaert, Gerben

AU - Sun, Lei

AU - Stroud, David A.

AU - Ho, Lena

N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15

PY - 2020/12/1

Y1 - 2020/12/1

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 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.

AB - 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.

UR - https://www.nature.com/articles/s41467-020-14999-2

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U2 - 10.1038/s41467-020-14999-2

DO - 10.1038/s41467-020-14999-2

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Abstract

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ASJC Scopus subject areas

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