2. Academic Validation
  3. RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis

RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis

  • EMBO J. 2025 Aug 26. doi: 10.1038/s44318-025-00533-x.
Monika Oláhová # 1 2,  Rachel M Guerra # 3,  Jack J Collier 4 5,  Juliana Heidler 6 7 8,  Kyle Thompson 4,  Chelsea R White 3,  Paulina Castañeda-Tamez 6 7,  Alfredo Cabrera-Orefice 6 7,  Robert N Lightowlers 9,  Zofia M A Chrzanowska-Lightowlers 9,  Alexander Galkin 10,  Ilka Wittig 6 7 11,  David J Pagliarini 3 12 13,  Robert W Taylor 14 15
Affiliations

Affiliations

  • 1 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. monika.winter@northumbria.ac.uk.
  • 2 Department of Applied Sciences, Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK. monika.winter@northumbria.ac.uk.
  • 3 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 4 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 5 Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
  • 6 Center for Functional Proteomics, Faculty of Medicine, Goethe University, 60590, Frankfurt am Main, Germany.
  • 7 Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe University, 60590, Frankfurt am Main, Germany.
  • 8 University Clinic of Vascular Surgery, Innsbruck Medical University, Anichstr. 35, A-6020, Innsbruck, Austria.
  • 9 Mitochondrial Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 10 Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, 10065, NY, USA.
  • 11 German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
  • 12 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 13 Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 14 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. robert.taylor@ncl.ac.uk.
  • 15 NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. robert.taylor@ncl.ac.uk.
  • # Contributed equally.
PMID: 40859035 DOI: 10.1038/s44318-025-00533-x
Abstract

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.

Keywords

Coenzyme Q; Complex I Assembly; Complexome Profiling; Mitochondria; RTN4IP1.

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