2026-09-23T10:56:16Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/277022026-09-12T00:16:10Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Khouili, Sofía C author Priego, Elena author Heras-Murillo, Ignacio author Dunphy, Gillian author Mastrangelo, Annalaura author Martínez-Cano, Sarai author Nuñez, Vanessa author Rodrigo-Tapias, Manuel author Belinchón-García, Adrián author Garaude, Johan author Iborra, Salvador author Chandel, Navdeep S author González-Rodríguez, Patricia author Enamorado, Michel author Sancho, David author 2026-05-29 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. Sci Immunol. 2026 May 29;11(119):eaef0098. SCIENCE IMMUNOLOGY 42172306 https://hdl.handle.net/20.500.12105/27702 Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.