Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction
The 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. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/836304v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1820147org.highwire.dtl.DTLVardef@21fad6org.highwire.dtl.DTLVardef@db22c1org.highwire.dtl.DTLVardef@c6ae5e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHeme synthesis inhibition changes mitochondrial morphology in endothelial cells C_LIO_LILoss of heme causes a buildup of mitochondrial ROS and depolarized membrane potential C_LIO_LIEndothelial cells have defective oxidative phosphorylation and glycolysis on loss of heme C_LIO_LIMitochondrial damage is caused by loss of functional heme-containing Complex IV and partially restored by exogenous heme C_LI