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Lookup NU author(s): Dr Charlotte Alston, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s), under exclusive licence to Springer Nature Limited 2024. Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.
Author(s): Sung AY, Guerra RM, Steenberge LH, Alston CL, Murayama K, Okazaki Y, Shimura M, Prokisch H, Ghezzi D, Torraco A, Carrozzo R, Rotig A, Taylor RW, Keck JL, Pagliarini DJ
Publication type: Article
Publication status: Published
Journal: Nature Metabolism
Year: 2024
Volume: 6
Pages: 1128–1142
Online publication date: 08/05/2024
Acceptance date: 28/03/2024
Date deposited: 22/05/2024
ISSN (electronic): 2522-5812
Publisher: Springer Nature
URL: https://doi.org/10.1038/s42255-024-01039-2
DOI: 10.1038/s42255-024-01039-2
ePrints DOI: 10.57711/2xqj-f839
Data Access Statement: All unique/stable reagents generated in this study are available upon request with a materials transfer agreement. The raw next-generation sequencing data from the DMS experiment have been deposited in the Sequence Read Archive (BioProject accession: PRJNA1007392). DMS variant and count data have been deposited on MaveDB (MaveDB accession: urn:mavedb:00000663-a). The raw proteomics data from the XL-MS experiment have been deposited in the MassIVE repository (MassIVE ID: MSV000094276). All deposited data are publicly available. Unprocessed image files and statistical data underlying the figures can be found in the source data files published alongside this manuscript. Code Availability: All original code has been deposited on GitHub (https://github.com/AYSung/af6-dms) and is publicly available.
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