The Role of ABCG2 and ABCB6 in Porphyrin Metabolism and Cell Survival

Abstract

The porphyrins (such as heme) are essential molecules within cells and have multiple roles in essential cellular processes such as: the mitochondrial electron transport chain, free-radical detoxification, and metabolism. The porphyrins need energy to traverse biological membranes. Our understanding of ABC transporters role in regulating intracellular porphyrin homeostasis is only now beginning to be understood. Two important contributors are members of the ABC transporter gene family: ABCB6 and ABCG2. ABCB6 is the first ABC transporter located in the outer mitochondrial membrane and oriented to facilitate porphyrin import. Consequently, ABCB6 can regulate and appropriately orchestrate porphyrin synthesis. This leads to an ability to regulate the amount of heme associated with heme requiring proteins. This ability can facilitate a cells protective response to an array of toxic insults. ABCG2 also binds and transports porphyrins, however its location at the plasma membrane provides a mechanism to remove excess porphyrins. Because ABCG2 is upregulated by hypoxia this provides a mechanism to export porphyrins, rebalance porphyrins and protect cells from porphyrin overaccumulation. Such a mechanism would be important to hypoxic cells which exhibit an increase in porphyrin synthesis under hypoxic conditions. Finally, we propose that these two transporters (ABCB6 and ABCG2) are coordinately regulated to modulate porphyrin concentrations under normal physiological and pathological conditions.

TMEM14C is required for erythroid mitochondrial heme metabolism

“…ABCB6 (EC3.6.3), a mitochondrial outer membrane protein, has been implicated as a putative mitochondrial importer of CPgenIII, enabling the conversion of CPgenIII to PPgenIX by inner membrane-bound CPOX in the intermembrane space (51)(52)(53)(54); although, more recent work suggests that it is dispensable for heme synthesis and specifies the blood group Langereis (55). Based on the colocalization of TMEM14C and CPOX, and the restricted role of TMEM14C in mitochondrial heme synthesis, we propose that TMEM14C directly accepts PPgenIX Chemical complementation assays.…”

Deficiency of ATP-Binding Cassette Transporter B6 in Megakaryocyte Progenitors Accelerates Atherosclerosis in Mice

“…Because ABCB6 has been involved in porphyrin transport, we next investigated the expression of genes involved in heme homeostasis. Interestingly, genes involved in heme synthesis pathway, such as δ-aminolevulinic acid dehydratase (AlaD), hydroxymethylbilane synthase (HMBS), ferrochelatase (FECH), and the porphyrin transporter ABCG2, 13 exhibited the same pattern of expression across the various BM and myeloid cells as ABCB6 ( Figure 1B). In contrast, heme oxygenase-1, the rate-limiting enzyme in heme catabolism and the heme sensor Rev-erbα, 14 was predominantly expressed in peritoneal macrophages ( Figure 1B).…”

Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

“…Second, Abcg2 loss may lead to increased intracellular accumulation of Abcg2 substrates, porphyrins [42][43][44][45] and glutathione [46], in turn, altering the stem cell redox state [47] and leading to activation of the stem cell niche [48,49]. The cellular redox status is crucial to the balance between stem/progenitor self-renewal and differentiation in various tissues [50].…”