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Lookup NU author(s): Dr Monika Olahova, Dr Jack Collier, Dr Kyle Thompson, Emeritus Professor Robert Lightowlers, Emerita Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.
Author(s): Olahova M, Guerra RM, Collier JJ, Heidler J, Thompson K, White CR, Castaneda-Tamez P, Cabrera-Orefice A, Lightowlers RN, Chrzanowska-Lightowlers ZMA, Galkin A, Wittig I, Pagliarini DJ, Taylor RW
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2025
Volume: 44
Pages: 5482-5508
Online publication date: 26/08/2025
Acceptance date: 22/07/2025
Date deposited: 09/09/2025
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1038/s44318-025-00533-x
DOI: 10.1038/s44318-025-00533-x
Data Access Statement: The proteomics and lipidomics data have been deposited to MassIVE repository (https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp) with the following link and study ID: MSV000098108. The mass spectrometry complexomics data together with a detailed description have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (Perez-Riverol et al, 2022) with the following dataset identifiers: PXD055511 and PXD064861. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-025-00533-x.
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