Abstract
Heme is an iron-containing porphyrin ring that serves as a prosthetic group in proteins that function in diverse metabolic pathways. Heme is also a major source of bioavailable iron in the human diet. While the synthesis of heme has been well-characterized, the pathways for heme trafficking remain poorly understood. It is likely that heme transport across membranes is highly regulated, as free heme is toxic to cells. This review outlines the requirement for heme delivery to various subcellular compartments as well as possible mechanisms for the mobilization of heme to these compartments. We also discuss how these trafficking pathways might function during physiological events involving inter- and intra-cellular mobilization of heme, including erythropoiesis, erythrophagocytosis, heme absorption in the gut, as well as heme transport pathways supporting embryonic development. Lastly, we aim to question the current dogma that heme, in toto, is not mobilized from one cell or tissue to another, outlining the evidence for these pathways and drawing parallels to other well-accepted paradigms for copper, iron, and cholesterol homeostasis.
Highlights
Heme is an iron-containing porphyrin that functions as a cofactor in a wide array of cellular processes
This review aims to (a) outline the biological requirement for heme trafficking pathways in eukaryotes, including the inability of heme to efficiently traverse lipid membranes and the presence of hemoproteins in almost all subcellular compartments, (b) summarize how these putative pathways may participate in various biological processes, including the synthesis and recycling of red blood cells (RBCs), intestinal absorption of dietary heme, embryogenesis, and (c) summarize the evidence for inter-cellular and inter-tissue transport of heme
Heme trafficking in iron metabolism by heme-binding proteins (HBPs), it is likely that this process would be regulated, as peroxidation of membrane lipids would result in severe damage, especially during a process such as erythropoiesis, with each red cell processing the heme required for over 300 million hemoglobin molecules
Summary
Heme is an iron-containing porphyrin that functions as a cofactor in a wide array of cellular processes. While the synthesis of heme has been wellcharacterized, the pathways for inter- and intra-cellular heme transport remain poorly understood This gap in our knowledge is largely due to the inability to uncouple the processes of heme biosynthesis and heme transport, as well as heme’s ability to promiscuously bind to proteins. This review aims to (a) outline the biological requirement for heme trafficking pathways in eukaryotes, including the inability of heme to efficiently traverse lipid membranes and the presence of hemoproteins in almost all subcellular compartments, (b) summarize how these putative pathways may participate in various biological processes, including the synthesis and recycling of red blood cells (RBCs), intestinal absorption of dietary heme, embryogenesis, and (c) summarize the evidence for inter-cellular and inter-tissue transport of heme. Even though heme is able to diffuse into membranes and be extracted www.frontiersin.org
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