The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease
Open accessPreprint — published as 10.1038/s42255-024-01039-2
Abstract
Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. Two-thirds of CI deficiencies arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of 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 add phenotypic annotation for 5,675 additional variants. Overall, our work defines the function of NDUFAF6 and provides a comprehensive clinical resource for diagnosing NDUFAF6-related diseases.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Pagliarini, D., Sung, A., Guerra, R., Steenberge, L., Alston, C., Murayama, K., Okazaki, Y., Shimura, M., Prokisch, H., Ghezzi, D., Torraco, A., Carrozzo, R., ROTIG, A., Taylor, R., & Keck, J.
- Affiliations
- Washington University in St. Louis (US)
- University of Wisconsin–Madison (US)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Juntendo University (JP)
- Helmholtz Munich (DE)
- University of Milan (IT)
- Bambino Gesù Children's Hospital (IT)
- INSERM U1163
- Corresponding author
- Pagliarini, David
- ORCID
- Venue
- Nature Metabolism
- Published
- 2023-11-16
- Volume
- 6
- Issue
- 6
- Pages
- 1128-1142
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC11395703
- OpenAlex
- W4396723770
- Cited by
- 23
- References
- 1
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 4
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Metabolism (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- mediaTUM (Technical University of Munich) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- U.S. Department of Health and Human Services (T32 AG000213, R35 GM131795, T32-GM140935, T32-GM008505)
- Japan Agency for Medical Research and Development (JP23ek0109625)
- Wellcome Trust
- Alvin J. Siteman Cancer Center (CA91842, #P30 CA91842)
- National Institute for Health and Care Research (203105/Z/16/Z, PDF-2018-11-ST2-021, MR/S005021/1)
- Department of Health and Social Care
- Bundesministerium für Bildung und Forschung (01GM1920A)
- Ministero della Salute (2018-, ERP-2019-23671045)
- National Institutes of Health (CA91842)
- Medical Research Council (G0800674, MR/S005021/1)
- Japan Society for the Promotion of Science (23H00424)
- National Institute on Aging (T32AG000213)
- National Cancer Institute (P30 CA 91842, CA91842, P30CA091842)
- National Institute of General Medical Sciences (T32GM008505, R35GM131795, T32GM140935)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- National Center for Research Resources (P30 CA91842)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- complex I assembly, NDUFS8, deep mutational scanning, variant pathogenicity, mitochondrial disease diagnosis, genetic variants
- MeSH terms
- Humans, Mitochondria, Mutation, Mitochondrial Proteins, Mitochondrial Diseases, Electron Transport Complex I
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