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 iΔEC ), but not of Mfn1 iΔEC , 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 iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2 iΔEC 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.