Heme oxygenase-1 is required for iron homeostasis and mitochondrial respiration

Jennifer Carr, Ping La, Phyllis Dennery. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S81, doi.org/10.1016/j.freeradbiomed.2018.10.182.

Heme is an essential cofactor in several enzymes of the electron transport chain (ETC) where its primary function is the coordination of iron to facilitate redox reactions. Unbound, free heme is strongly oxidative such that the cell has evolved mechanisms to prevent it from causing oxidative damage. This includes the catalytic breakdown of heme by heme oxygenase (HO-1), generating antioxidants CO and biliverdin. However the catabolism of heme also releases highly toxic free iron which seems counter productive to the antioxidant effort. We sought to explore the role of HO-1 in iron homeostasis using HO-1 knockout mouse embryonic fibroblasts and HO-1 deficient human liver cells. By Western blot these cells showed dysregulated iron handling including increased expression of transferrin receptor and decreased expression of ferritin and ferroportin compared to wild type controls. Additionally cytosolic aconitase activity was decreased in HO-1 deficient cells while the mutually exclusive mRNA binding activity of aconitase was increased. This switch is indicative of reduced FeS cluster availability. Consistent with FeS cluster deficiency we observed decreased frataxin mRNA levels, the product of which is involved in FeS cluster assembly in the mitochondria. Because FeS clusters are important in the ETC we examined mitochondrial respiration with a Seahorse Bioanalyzer (Agilent) and found it to be markedly reduced in HO-1 knockout cells. Interestingly, this was partially rescued by exogenous iron (1nM transferrin). Our findings suggest that an additional and important role of HO-1 is the maintenance of cellular iron homeostasis via the release of iron upon breakdown of heme.