Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Abstract

AbstractThe relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.Abstract FigureHighlightsHeme synthesis inhibition changes mitochondrial morphology in endothelial cellsLoss of heme causes a buildup of mitochondrial ROS and depolarized membrane potentialEndothelial cells have defective oxidative phosphorylation and glycolysis on loss of hemeMitochondrial damage is caused by loss of functional heme-containing Complex IV and partially restored by exogenous heme