Professor Iqbal Hamza, University of Maryland School of Medicine (U.S.)

Heme is an indispensable yet potentially toxic cofactor that underlies diverse biological processes, including gas signaling, microRNA maturation, and xenobiotic metabolism. Although synthesized in the mitochondria of most eukaryotes, free heme is hydrophobic and catalytically reactive, requiring tightly regulated systems for its transport and utilization. The nematode C. elegans, which lacks the ability to synthesize heme, acquires environmental heme to support hemoproteins conserved in higher organisms, providing a powerful genetic model for studying heme homeostasis. Genetic screens in C. elegans identified Heme Responsive Genes (HRGs), including HRG1, the first eukaryotic heme transporter, which was later shown to be essential for heme recovery during erythrophagocytosis in mammals. Strikingly, HRG1-deficient mice survive despite massive heme accumulation by polymerizing heme into inert hemozoin crystals within macrophage lysosomes. This adaptive mechanism reveals a previously unrecognized mammalian heme detoxification pathway, suggesting that natural HRG1 variants may modulate susceptibility to heme-driven pathologies such as hemolytic disease.