Control of Metazoan Heme Homeostasis by a Conserved Multidrug Resistance Protein

Several lines of evidence predict that specific pathways must exist in metazoans for the escorted movement of heme, an essential but cytotoxic iron-containing organic ring, within and between cells and tissues, but these pathways remain obscure. In Caenorhabditis elegans, embryonic development is inextricably dependent on both maternally derived heme and environmentally acquired heme. Here, we show that the multidrug resistance protein MRP-5/ABCC5 likely acts as a heme exporter, and targeted depletion of mrp-5 in the intestine causes embryonic lethality. Transient knockdown of mrp5 in zebrafish leads to morphological defects and failure to hemoglobinize red blood cells. MRP5 resides on the plasma membrane and endosomal compartments and regulates export of cytosolic heme. Together, our genetic studies in worms, yeast, zebrafish, and mammalian cells identify a conserved, physiological role for a multidrug resistance protein in regulating systemic heme homeostasis. We envision other MRP family members may play similar unanticipated physiological roles in animal development. [Display omitted] •Pathways for subcellular heme trafficking are critical but poorly understood•C. elegans mrp-5 is required for export of intestinal heme to extraintestinal tissues•Loss of MRP5 in C. elegans and zebrafish causes lethality and anemia, respectively•In mammals, MRP5 regulates export of cytoplasmic heme into the secretory pathway Heme is an essential cofactor for life but if misregulated can be cytotoxic. How exogenous or intracellular heme is trafficked to subcellular destinations remains largely unexplored. Here, Korolnek et al. use genetic studies in yeast, worms, zebrafish, and mammalian cells to show that the multidrug resistance protein MRP-5/ABCC5 is an essential regulator of heme export.