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Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function

Lookup NU author(s): Dr Charlotte Alston, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function.


Publication metadata

Author(s): Floyd BJ, Wilkerson EM, Veling MT, Minogue CE, Xia CW, Beebe ET, Wrobel RL, Cho H, Kremer LS, Alston CL, Gromek KA, Dolan BK, Ulbrich A, Stefely JA, Bohl SL, Werner KM, Jochem A, Westphall MS, Rensvold JW, Taylor RW, Prokisch H, Kim JJP, Coon JJ, Pagliarini DJ

Publication type: Article

Publication status: Published

Journal: Molecular Cell

Year: 2016

Volume: 63

Issue: 4

Pages: 621-632

Print publication date: 18/08/2016

Online publication date: 04/08/2016

Acceptance date: 21/06/2016

Date deposited: 31/10/2016

ISSN (print): 1097-2765

ISSN (electronic): 1097-4164

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.molcel.2016.06.033

DOI: 10.1016/j.molcel.2016.06.033


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Funding

Funder referenceFunder name
Lily Foundation
NSF
Searle Scholars Award
Wisconsin Distinguished Graduate Fellowship
UK NHS Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
01GM1113CGerman Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET)
01GM1603E-Rare project GENOMIT
096919/Z/11/ZWellcome Trust
317433EC FP7-PEOPLE-ITN Mitochondrial European Educational Training Project (GA)
633974EU
F30AG043282NIH
G0601943MRC Centre for Neuromuscular Diseases
R01DK098672NIH
NIHR-HCS-D12-03-04National Institute for Health Research (NIHR)
R01GM112057NIH
R35GM118110NIH
T32DK007665NIH
T32GM008692 MSTPNIH
T32GM07215NIH
T32HL007899NIH
R01GM029076NIH
R01GM115591NIH
T15LM007359NIH
U01GM94622NIH

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