RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis
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.
Authors
- Robert N. Lightowlers (ORCID: https://orcid.org/0000-0002-0587-9937)
- Ilka Wittig (ORCID: https://orcid.org/0000-0002-9751-8054)
- Rachel M. Guerra (ORCID: https://orcid.org/0000-0002-0729-5564)
- Alexander Galkin (ORCID: https://orcid.org/0000-0001-8469-2283)
- Chelsea R. White
- Zofia M. Chrzanowska‐Lightowlers (ORCID: https://orcid.org/0000-0002-0045-3152)
- Kyle Thompson (ORCID: https://orcid.org/0000-0002-2868-7612)
- Monika Oláhová (ORCID: https://orcid.org/0000-0002-4082-3875)
- David J. Pagliarini (ORCID: https://orcid.org/0000-0002-0001-0087)
- Jack J. Collier (ORCID: https://orcid.org/0000-0001-6282-0301)
- Paulina Castañeda-Támez
- Alfredo Cabrera‐Orefice (ORCID: https://orcid.org/0000-0002-2042-3794)
- Robert William Taylor (ORCID: https://orcid.org/0000-0002-7768-8873)
- Juliana Heidler (ORCID: https://orcid.org/0009-0003-5315-314X)
Institutions
- Goethe University Frankfurt (DE)
- Innsbruck Medical University (AT)
- Washington University in St. Louis (US)
- Cornell University (US)
- University of Cambridge (GB)
- Frankfurt Institute for Advanced Studies (DE)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Northumbria University (GB)
- MIND Research Institute (US)
- German Centre for Cardiovascular Research (DE)
- Wellcome Centre for Mitochondrial Research (GB)
- Weill Cornell Medicine (US)
- Saint Louis University (US)
- Newcastle University (GB)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1038/s44318-025-00533-x
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- LifeArc
- Biochemical Society
- Fight for Sight UK
- Pathological Society of Great Britain and Ireland
- Academy of Medical Sciences
- Deutsche Forschungsgemeinschaft
- Mito Foundation
- Lily Foundation
- National Institutes of Health
- NIHR Newcastle Biomedical Research Centre