Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells
Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD + /NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD + /NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD + /NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD + -driven redox metabolism, and antigen cross-presentation.
Authors
- Gillian Dunphy (ORCID: https://orcid.org/0000-0003-0991-4565)
- Patricia González‐Rodríguez (ORCID: https://orcid.org/0000-0002-2561-3984)
- Annalaura Mastrangelo (ORCID: https://orcid.org/0000-0003-2650-0444)
- Navdeep S. Chandel (ORCID: https://orcid.org/0000-0001-7208-3886)
- Johan Garaude (ORCID: https://orcid.org/0000-0001-7789-7715)
- David Sancho (ORCID: https://orcid.org/0000-0003-2890-3984)
- Ignacio Heras‐Murillo (ORCID: https://orcid.org/0000-0002-8797-8786)
- Sarai Martínez-Cano (ORCID: https://orcid.org/0000-0001-5883-3900)
- Michel Enamorado (ORCID: https://orcid.org/0000-0001-7748-454X)
- Salvador Iborra (ORCID: https://orcid.org/0000-0002-1607-1749)
- Elena Priego (ORCID: https://orcid.org/0000-0002-7560-0620)
- Manuel Rodrigo-Tapias (ORCID: https://orcid.org/0009-0009-6490-3114)
- Vanessa Nuñez (ORCID: https://orcid.org/0000-0002-7473-1514)
- Sofía C. Khouili (ORCID: https://orcid.org/0000-0002-7333-789X)
- Adrián Belinchón-García (ORCID: https://orcid.org/0009-0001-0313-2370)
Institutions
- Northwestern University (US)
- Universidad Complutense de Madrid (ES)
- Centre National de la Recherche Scientifique (FR)
- Allen Institute for Brain Science (US)
- Inserm (FR)
- Instituto de Salud Carlos III (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Centre National pour la Recherche Scientifique et Technique (CNRST) (MA)
- Inmunotek (Spain) (ES)
- Instituto de Biomedicina de Sevilla (ES)
- Universidad Alfonso X el Sabio (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Universidad de Sevilla (ES)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1126/sciimmunol.aef0098
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Icahn School of Medicine at Mount Sinai
- Worldwide Cancer Research
- Comunidad de Madrid
- Ministerio de Ciencia, Innovación y Universidades
- Fundación Científica Asociación Española Contra el Cáncer
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- European Research Council