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Sung, A.Y.* ; Guerra, R.M.* ; Steenberge, L.H.* ; Alston, C.L.* ; Murayama, K.* ; Okazaki, Y.* ; Shimura, M. ; Prokisch, H. ; Ghezzi, D.* ; Torraco, A.* ; Carrozzo, R.* ; Rötig, A.* ; Taylor, R.W.* ; Keck, J.L.* ; Pagliarini, D.J.*

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Nat. Metab., DOI: 10.1038/s42255-024-01039-2 (2024)
DOI PMC
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Leigh-syndrome; Association; Deficiency; Mutations; Mechanism; Sequences; Enzymes; Genes; Cells
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants NIH Roadmap for Medical Research
NIH
BJC Investigator Program
NIHR
Wellcome Centre for Mitochondrial Research
Mitochondrial Disease Patient Cohort grant
Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease
Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development
Italian Ministry of Health
German Federal Ministry of Education and Research
European Joint Programme on Rare Diseases project GENOMIT
NCI Cancer Center Support Grant
Siteman Cancer Center from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH)
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)