Control of Metazoan Heme Homeostasis by a Conserved Multidrug Resistance Protein

Abstract

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.

The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans

“…Mutant rde-1 worms are resistant to RNAi, but restoring tissue-specific expression of the wild-type rde-1 cDNA in these mutants confers RNAi sensitivity to a specific tissue (27). We depleted cua-1 in wildtype N2, WM27 (rde-1 mutant, RNAi insensitive), VP303 (P nhx-2 ::RDE-1, intestine only RNAi), WM118 (P myo-3 ::RDE-1, muscle only RNAi), and NR222 (P lin-26 ::RDE-1, hypodermis only RNAi) worm strains (13). Knockdown of cua-1 in the intestine resulted in reduced fecundity similar to that of wholebody RNAi (Fig.…”

“…For these reasons, we utilized C. elegans, which has been widely used in the study of the metabolism of other metals, including iron, heme, and zinc (8,(13)(14)(15)(16)(17). Although mammals have two copper exporters, serving complementary functions in different tissues such as the gut and liver, lower metazoans (including nematodes (C. elegans) and insects (Drosophila melanogaster)) have only a single homolog of ATP7A/B (2,18,19).…”

Regulation of heme biosynthesis and transport in metazoa

“…Korolnek et al [73] identified the multidrug resistance protein MRP-5/ABCC5 as another heme exporter in animals. In C. elegans, MRP-5 localizes to the basolateral surface of the intestinal cells and mediates heme export out of the intestine.…”

“…In C. elegans, MRP-5 localizes to the basolateral surface of the intestinal cells and mediates heme export out of the intestine. Deletion of mrp-5 results in embryonic death, which is due to impaired heme transfer to extra-intestinal tissues [73]. In vertebrate cells, MRP-5 localizes to both plasma membrane and intracellular compartments [73].…”

“…In vertebrate cells, MRP-5 localizes to both plasma membrane and intracellular compartments [73]. Deficiency of mrp-5 led to reduced heme loading into the secretory compartments in mouse embryonic fibroblasts and profound anemia in zebrafish embryos [73].…”