Heme-binding Protein HRG-1 Is Induced by Insulin-like Growth Factor I and Associates with the Vacuolar H+-ATPase to Control Endosomal pH and Receptor Trafficking

Background:The role of the mitochondrial ABC transporter, Abcb6, in vivo is unknown. Results: Abcb6-null mice are incapable of ATP-dependent import of mitochondrial porphyrins. Despite compensatory changes in the porphyrin pathway, Abcb6-null mice are less viable after a porphyrin-inducing stress. Conclusion: Abcb6 absence abolished ATP-dependent mitochondrial porphyrin uptake and deregulated porphyrin pathway genes. Significance: Disrupted Abcb6 function may produce porphyria after certain stresses.

Section: Discussionmentioning

confidence: 99%

ATP-dependent Mitochondrial Porphyrin Importer ABCB6 Protects against Phenylhydrazine Toxicity

Ulrich

Lynch

Wang

et al. 2012

“…Another mechanism could be coupling with an energetically favorable flow or counterflow of ion gradients generated by primary transporters, a feature characteristic of permeases. Indeed, a recent study demonstrated that human HRG-1 associates with the V-ATPase proton pump (39), suggesting the possibility that a proton gradient generated by V-ATPases may drive heme transport, similar to the endocytic calcium transporters in yeast (40).…”

Section: Discussionmentioning

confidence: 99%

Topologically Conserved Residues Direct Heme Transport in HRG-1-related Proteins

Yuan

Protchenko

Philpott

et al. 2012

111

Background: HRG-1-related proteins have low sequence homology but are functionally conserved. Results: Conserved residues within the transmembrane domain and the C terminus dictate the function of HRG-1-related proteins. Conclusion: Heme transport is mediated by topologically conserved residues implying an evolutionary ancient transport mechanism. Significance: Understanding the mechanism of HRG-1-related protein function will provide novel therapeutic insights into human hematological disorders and parasites, which rely on host heme for survival.

“…The HRG-4 permease is responsible for bringing heme into cells in worms, but nothing is known regarding how that heme is imported into the mitochondria. Likewise, human cells have a HRG-4 ortholog HRG-1 that resides within endocytic vesicles and facilitates heme import into the cytoplasm (16,29). HRG-1 is known to mediate heme transport from phagolysosomes of macrophages to the cytoplasm compartment during erythrophagocytosis in a process of iron recycling (30).…”

Section: Discussionmentioning

confidence: 99%

The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria

Kim

Jeong

Parnell

et al. 2016

The cellular transport of the cofactor heme and its biosynthetic intermediates such as protoporphyrin IX is a complex and highly coordinated process. To investigate the molecular details of this trafficking pathway, we created a synthetic lesion in the heme biosynthetic pathway by deleting the gene HEM15 encoding the enzyme ferrochelatase in S. cerevisiae and performed a genetic suppressor screen. Cells lacking Hem15 are respiratory-defective because of an inefficient heme delivery to the mitochondria. Thus, the biogenesis of mitochondrial cytochromes is negatively affected. The suppressor screen resulted in the isolation of respiratory-competent colonies containing two distinct missense mutations in Nce102, a protein that localizes to plasma membrane invaginations designated as eisosomes. The presence of the Nce102 mutant alleles enabled formation of the mitochondrial respiratory complexes and respiratory growth in hem15⌬ cells cultured in supplemental hemin. Respiratory function in hem15⌬ cells can also be restored by the presence of a heterologous plasma membrane heme permease (HRG-4), but the mode of suppression mediated by the Nce102 mutant is more efficient. Attenuation of the endocytic pathway through deletion of the gene END3 impaired the Nce102-mediated rescue, suggesting that the Nce102 mutants lead to suppression through the yeast endocytic pathway.Heme is an essential cofactor in eukaryotes and bacteria and functions in a myriad of pathways including oxygen transport, nitric oxide and carbon monoxide sensing, oxygenase reactions, and electron transport reactions (1-3). The heme biosynthetic pathway in eukaryotes, including the yeast Saccharomyces cerevisiae, is a complex process involving eight enzymes (see Fig. 1A) (4). The process starts in the mitochondrial matrix with the condensation of glycine with succinyl-CoA to produce ∂-aminolevulinic acid (ALA) 3 by the enzyme 5-aminolevulinate synthase (Hem1 is the yeast designation) (2, 4). ALA is translocated across the mitochondrial membranes to the cytosol, where the next four enzymes in the pathway convert two ALA molecules to form the intermediate pyrrole porphobilinogen and subsequent formation of coproporphyrinogen III, which is transported back into the mitochondria for conversion to protoporphyrin IX (PPIX). Ferrous iron is inserted into PPIX by ferrochelatase (Hem15), tethered to the inner membrane and facing the matrix, to form the heme cofactor. A defect in any of heme biosynthetic enzymes leads to one of the porphyric disorders in humans, each with a unique phenotype resulting from a buildup of toxic intermediates (3).The mechanism of heme transport between cellular compartments remains poorly understood (4). Nevertheless, significant inroads have been recently made utilizing the heme auxotroph Caenorhabditis elegans, resulting in the identification of heme and porphyrin transporters, including the HRG-1-related heme transporters (4, 5). These transporters have mammalian homologs with similar function and specificity. Additionally, the fel...