Heme trafficking: Lessons from Bloodless Worms

Heme is an indispensable yet potentially toxic cofactor that underpins diverse biological processes, including gas signaling, microRNA maturation, and xenobiotic metabolism. While synthesized in the mitochondria of most eukaryotes, free heme is hydrophobic and catalytically reactive, necessitating tightly regulated systems for its trafficking and utilization. The nematode C. elegans, which lacks heme synthesis, acquires environmental heme to support hemoproteins conserved in higher organisms, providing a powerful genetic model to dissect heme homeostasis. Genetic screens in C. elegans uncovered Heme Responsive Genes (HRGs), including HRG1, the first eukaryotic heme transporter, 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. Finally, recent advances in our understanding of a novel role for HRG1 in heme acquisition by erythroid cells under stress will be discussed.