FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression is protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 deficiency impaired basal mitophagy in endothelial cells, leading to accumulation of dysfunctional mitochondria, metabolic reprogramming towards aerobic glycolysis, pseudohypoxia and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, Fundc1-deficient endothelial cells increased IGFBP2 secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence or IGFBP2. Overall design: Single-cell suspensions from NW,NK,HSW,HSK proup were analyzed using scRNAseq. We use the HySu (hypoxia and SU5416) PH model. The HySu mice received 3 weekly doses of SU5416. SU5416 was resuspended in a carboxymethylcellulose solution (wt/vol: 0.5% carboxymethylcellulose sodium, 0.9% sodium chloride, 0.4% polysorbate 80, and 0.9% benzyl alcohol in water). Control groups were administered with the same volume of vehicle and kept under normoxia.Single lung cell suspensions from Normoxia-WT (NW), Normoxia-FUNDC1-KO (NK), HySu-WT (HSW), HySu-FUNDC1-KO (HSK) group were analyzed using scRNAseq.