Heme Mobilization in Animals: A Metallolipid's Journey

Abstract

Heme is universally recognized as an essential and ubiquitous prosthetic group that enables proteins to carry out a diverse array of functions. All heme-dependent processes, from protein hemylation to heme signaling, require the dynamic and rapid mobilization of heme to hemoproteins present in virtually every subcellular compartment. The cytotoxicity and hydrophobicity of heme necessitates that heme mobilization is carefully controlled at the cellular and systemic level. However, the molecules and mechanisms that mediate heme homeostasis are poorly understood. In this Account, we provide a heuristic paradigm with which to conceptualize heme trafficking and highlight the most recent developments in the mechanisms underlying heme trafficking. As an iron-containing tetrapyrrole, heme exhibits properties of both transition metals and lipids. Accordingly, we propose its transport and trafficking will reflect principles gleaned from the trafficking of both metals and lipids. Using this conceptual framework, we follow the flow of heme from the final step of heme synthesis in the mitochondria to hemoproteins present in various subcellular organelles. Further, given that many cells and animals that cannot make heme can assimilate it intact from nutritional sources, we propose that intercellular heme trafficking pathways must exist. This necessitates that heme be able to be imported and exported from cells, escorted between cells and organs, and regulated at the organismal level via a coordinated systemic process. In this Account, we highlight recently discovered heme transport and trafficking factors and provide the biochemical foundation for the cell and systems biology of heme. Altogether, we seek to reconceptualize heme from an exchange inert cofactor buried in hemoprotein active sites to an exchange labile and mobile metallonutrient.

Figure 1

Lipid-like properties of heme. The “phospholipid-like” structure of heme is depicted alongside the other mitochondrial-derived lipids phosphatidylethanolamine (PE) and cardiolipin (CL).

Figure 2

Mechanisms of lipid trafficking. Heme may be trafficked by mechanisms analogous to that of other lipids, including by diffusion, vesicular transport, carrier proteins, and at membrane contact sites. Sites of membrane contact are facilitated by supramolecular protein assemblies, e.g., the endoplasmic reticulum-mitochondia encounter structure (ERMES) complex, that are located at the interface of two organelles and act to tether them together.

Figure 3

Intracellular heme transport and trafficking in eukaryotes. Once heme (red crosses) is biosynthesized on the matrix side of the mitochondrial inner membrane, it must transit to (1) soluble matrix proteins, (2) inner membrane proteins, (3) soluble intermembrane space (IMS) proteins, or (4) outside the mitochondria. Once in the cytosol, labile heme, which is buffered in part by the factors indicated in green, must be trafficked to (5) cytosolic, (6) nuclear, and (7) endoplasmic reticulum (ER) and golgi proteins. Alternatively, heme can be trafficked to other locales via (8) mitochondrial-derived vesicles (MDVs) or (9) mitochondria-ER contact points. Known heme transport and trafficking factors are highlighted.

Figure 4

Heme homeostasis pathways identified using the C. elegans model. HRG-1 paralogues (HRG-1, HRG-4) import heme into the intestine from the apical surface. Heme export from the basolateral surface of the intestine is mediated by MRP-5, an ABC transporter. The peptide HRG-3 is secreted by the mother's intestine and functions to transport maternal heme to developing oocytes and other extra-intestinal tissues. HRG-2 is a putative heme reductase, which facilitates heme uptake in the hypodermis.