One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers

Abstract

Heme, as a hydrophobic iron-containing organic ring, is lipid soluble and can interact with biological membranes. The very same properties of heme that nature exploits to support life also renders heme potentially cytotoxic. In order to utilize heme, while also mitigating its toxicity, cells are challenged to tightly control the concentration and bioavailability of heme. On the bright side, it is reasonable to envision that, analogous to other transition metals, a combination of membrane-bound transporters, soluble carriers, and chaperones coordinate heme trafficking to subcellular compartments. However, given the dual properties exhibited by heme as a transition metal and lipid, it is compelling to consider the dark side: the potential role of non-proteinaceous biomolecules including lipids and nucleic acids that bind, sequester, and control heme trafficking and bioavailability. The emergence of inter-organellar membrane contact sites, as well as intracellular vesicles derived from various organelles, have raised the prospect that heme can be trafficked through hydrophobic channels. In this review, we aim to focus on heme delivery without deliverers - an alternate paradigm for the regulation of heme homeostasis through chaperone-less pathways for heme trafficking.

Keywords: Heme; Iron; Porphyrin; Tetrapyrrole; Trafficking.

Figure 1.

Consensus model of known proteinaceous mechanisms for metazoan heme transport and trafficking within and between cells. Intracellular heme is either produced via de novo synthesis in the mitochondria or imported via transporters or endocytosis (green components). The efflux of heme to exoplasmic spaces is mediated by transporters or exocytosis (blue components). The labile heme pool (LHP) consists of heme that is buffered by a network of proteins and facilitates its trafficking to other organelles throughout the cell. In mammals, FLVCR2 has been implicated as a plasma membrane heme importer, whereas LRP1 and CD163 are cell surface scavenger receptors for hemopexin (HPX) and the haptoglobin-hemoglobin (HP) complex (or hemoglobin alone), respectively. Heme is also transported via endocytosis of senescent red blood cells (RBCs) and shed microvesicles (MVs) or exosomes in vertebrates. In worms, HRG-4 homologs are dedicated plasma membrane importers and HRG-2 aids in heme utilization by functioning as an oxidoreductase. Finally, heme is imported into the cytosol from exoplasmic compartments via HRG1 and FLVCR1b at the endolysosome and mitochondria, respectively. Conversely, heme efflux is primarily achieved via plasma membrane exporters FLVCR1a, ABCG2 and MRP5 in mammals, with MRP5 also having been localized to the secretory pathway for heme efflux from the cytosol across metazoans. In worms, heme additionally is secreted from intestinal cells for intercellular heme transport via the heme binding protein HRG-3, while interorgan heme homeostasis is modulated via secretion of HRG-7. Created with BioRender - see text for additional details and Table 1.

Figure 2.

Proposed model for “chaperone-less” heme trafficking via inter-organelle membrane contact sites (highlighted in green) and G-quadruplexes. The specific organellar contact sites, numbered 1–7, are described in Table 2. RNA and DNA G-quadruplexes are also hypothesized to regulate intracellular heme bioavailability.

Figure 3.

Cartoon of the ER-mitochondrial encounter structure (ERMES) in yeast, which facilitates calcium and phospholipid exchange, as well as possibly heme trafficking. ERMES consists of four proteins, Mdm12, Mmm1, Mdm34, and Mdm10, that physically tether the ER and outer mitochondrial membranes. Gem1 is a GTPase that disengages ERMES after mitochondrial fission. Altering the frequency of ERMES, by deletion of Gem1, or GTPases that control mitochondrial fusion, e.g. Mgm1, and fission, e.g. Dnm1, has been shown to affect mitochondrial-nuclear heme trafficking rates. See text for details.