Heme Trafficking and the Importance of Handling Nature’s Most Versatile Cofactor

Heme is one of the most versatile cofactors in nature from its role in oxygen transport and sensing, bioenergetics, and enzyme catalysis and is therefore an ideal regulatory molecule in responding to the redox status of the cell. However, due to both its redox reactivity and hydrophobicity, heme requires tight regulation at the level of its synthesis and degradation. Increasingly, the role of heme as a signaling and regulatory molecule and the tight regulation of heme biosynthesis and degradation beg the question of how heme is trafficked for optimal distribution and biological function. Herein we review the current understanding of heme trafficking in the context of its role as a regulatory molecule, the labile exchange of heme, and its integration into the overall regulation of heme biosynthesis and degradation. Additionally, the critical role of heme in metabolic regulation, cardiovascular function, and the immune response underscores a greater need to understand the complex regulatory roles of heme and the consequence of its dysregulation in a variety of disease states.