Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice
Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2<sup>iΔEC</sup>), but not of Mfn1<sup>iΔEC</sup>, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2<sup>iΔEC</sup> mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2<sup>iΔEC</sup> mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.
Authors
- Arnaud Obri (ORCID: https://orcid.org/0000-0002-0779-1082)
- Iasim Tahiri
- Josep Maria Roncero Vidal
- Alícia G. Gómez-Valadés (ORCID: https://orcid.org/0000-0002-4088-1338)
- Erika Monelli (ORCID: https://orcid.org/0000-0002-0541-0602)
- Júlia Fos-Domènech
- Markus Haake (ORCID: https://orcid.org/0009-0008-3353-7919)
- Abdiel Alvarado-Díaz
- Claude Knauf (ORCID: https://orcid.org/0000-0001-5213-5378)
- Marc Claret (ORCID: https://orcid.org/0000-0001-7766-9296)
- Pilar Villacampa (ORCID: https://orcid.org/0000-0002-2860-7475)
- Óscar Osorio-Conles (ORCID: https://orcid.org/0000-0002-0285-5526)
- Íñigo Chivite (ORCID: https://orcid.org/0000-0002-2201-9998)
- Sara Ramírez (ORCID: https://orcid.org/0000-0002-2072-2495)
- Francisco Díaz-Castro
- Ruben Nogueiras
- Katrien De Bock
- Xavier Remesar
- Macarena Pozo
- Francesc Ventura
- Anne Abot
- Sabrina Genßler
- Tamas L. Horvath
- Jordi Altirriba
- Christine Schuberth-Wagner
- Roberta Haddad-Tóvolli
- Mariona Graupera
- Miriam Toledo
- Elena Eyre
- Pablo M. Garcia-Rovés
- Chloé van Gelder
- Pau García-Ramón
- Maria Milà-Guasch
- Margalida Munar-Gelabert
- Jorge Alvarez Luis
- José Antonio Valer
- Luis Varela
- Antonio Zorzano
- Mariana Ferreira
Institutions
- Universidade da Coruña (ES)
- University of Geneva (CH)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Bellvitge University Hospital (ES)
- Yale University (US)
- ETH Zurich (CH)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Institut de Recherche en Santé Digestive (FR)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Max Planck Institute of Biochemistry (DE)
- Instituto de Investigación Biomédica de A Coruña (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2026-02-17
- DOI
- https://doi.org/10.1016/j.cmet.2026.01.012
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00