Molecular Mechanisms of Iron and Heme Metabolism

Literature Cited

1. 1.

   Adams PA, Berman MC. 1980. Kinetics and mechanism of the interaction between human serum albumin and monomeric haemin. Biochem. J. 191:195–102
   [Google Scholar]
2. 2.

   Altamura S, Vegi NM, Hoppe PS, Schroeder T, Aichler M et al. 2020. Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis. Haematologica 105:4937–50
   [Google Scholar]
3. 3.

   Andolfo I, Rosato BE, Manna F, Rosa GD, Marra R et al. 2020. Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway. Am. J. Hematol. 95:2188–97
   [Google Scholar]
4. 4.

   Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E et al. 2005. Hemoglobin and heme scavenging. IUBMB Life 57:11749–59
   [Google Scholar]
5. 5.

   Ashouri R, Fangman M, Burris A, Ezenwa MO, Wilkie DJ, Doré S. 2021. Critical role of hemopexin mediated cytoprotection in the pathophysiology of sickle cell disease. Int. J. Mol. Sci. 22:126408
   [Google Scholar]
6. 6.

   Ast T, Meisel JD, Patra S, Wang H, Grange RMH et al. 2019. Hypoxia rescues frataxin loss by restoring iron sulfur cluster biogenesis. Cell 177:61507–21.e16
   [Google Scholar]
7. 7.

   Balla J, Zarjou A. 2021. Heme burden and ensuing mechanisms that protect the kidney: insights from bench and bedside. Int. J. Mol. Sci. 22:158174
   [Google Scholar]
8. 8.

   Billesbølle CB, Azumaya CM, Kretsch RC, Powers AS, Gonen S et al. 2020. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature 586:7831807–11
   [Google Scholar]
9. 9.

   Braymer JJ, Freibert SA, Rakwalska-Bange M, Lill R. 2021. Mechanistic concepts of iron-sulfur protein biogenesis in biology. Biochim. Biophys. Acta Mol. Cell Res. 1868:1118863
   [Google Scholar]
10. 10.

    Bryk AH, Wiśniewski JR. 2017. Quantitative analysis of human red blood cell proteome. J. Proteome Res. 16:82752–61
    [Google Scholar]
11. 11.

    Castro-Mollo M, Gera S, Ruiz-Martinez M, Feola M, Gumerova A et al. 2021. The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry. eLife 10:e68217
    [Google Scholar]
12. 12.

    Chambers I, Kumar P, Lichtenberg J, Wang P, Yu J et al. 2021. MRP5 and MRP9 play a concerted role in male reproduction and mitochondrial function. PNAS 119:6e2111617119
    [Google Scholar]
13. 13.

    Chambers IG, Willoughby MM, Hamza I, Reddi AR. 2021. One ring to bring them all and in the darkness bind them: the trafficking of heme without deliverers. Biochim. Biophys. Acta Mol. Cell Res. 1868:1118881
    [Google Scholar]
14. 14.

    Chen C, Samuel TK, Sinclair J, Dailey HA, Hamza I. 2011. An intercellular heme-trafficking protein delivers maternal heme to the embryo during development in C. elegans. Cell 145:5720–31
    [Google Scholar]
15. 15.

    Chen J-J, Zhang S. 2019. Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies. Blood 134:201697–707
    [Google Scholar]
16. 16.

    Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S et al. 2012. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J. Clin. Investig. 122:124569–79
    [Google Scholar]
17. 17.

    Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. 2014. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharmacol. 5:61
    [Google Scholar]
18. 18.

    Colucci S, Marques O, Altamura S. 2021. 20 years of Hepcidin: How far we have come. Semin. Hematol. 58:3132–44
    [Google Scholar]
19. 19.

    Consoli V, Sorrenti V, Grosso S, Vanella L. 2021. Heme oxygenase-1 signaling and redox homeostasis in physiopathological conditions. Biomolecules 11:4589
    [Google Scholar]
20. 20.

    Coronado LM, Nadovich CT, Spadafora C. 2014. Malarial hemozoin: from target to tool. Biochim. Biophys. Acta Gen. Subj. 1840:62032–41
    [Google Scholar]
21. 21.

    Corradini E, Buzzetti E, Pietrangelo A. 2020. Genetic iron overload disorders. Mol. Aspects Med. 75:100896
    [Google Scholar]
22. 22.

    Corral VM, Schultz ER, Eisenstein RS, Connell GJ. 2021. Roquin is a major mediator of iron-regulated changes to transferrin receptor-1 mRNA stability. iScience 24:4102360
    [Google Scholar]
23. 23.

    Crispin A, Guo C, Chen C, Campagna DR, Schmidt PJ et al. 2020. Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia. J. Clin. Investig. 130:105245–56
    [Google Scholar]
24. 24.

    Dai Y, Sweeny EA, Schlanger S, Ghosh A, Stuehr DJ. 2020. GAPDH delivers heme to soluble guanylyl cyclase. J. Biol. Chem. 295:248145–54
    [Google Scholar]
25. 25.

    Das NK, Schwartz AJ, Barthel G, Inohara N, Liu Q et al. 2020. Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab 31:1115–30.e6
    [Google Scholar]
26. 26.

    Delanghe JR, Langlois MR. 2001. Hemopexin: a review of biological aspects and the role in laboratory medicine. Clin. Chim. Acta 312:1–213–23
    [Google Scholar]
27. 27.

    Dietz JV, Willoughby MM, Piel RB, Ross TA, Bohovych I et al. 2021. Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase. Redox Biol 46:102125
    [Google Scholar]
28. 28.

    Donegan RK, Moore CM, Hanna DA, Reddi AR. 2019. Handling heme: the mechanisms underlying the movement of heme within and between cells. Free Radic. . Biol. Med. 133:88–100
    [Google Scholar]
29. 29.

    Duffy SP, Shing J, Saraon P, Berger LC, Eiden MV et al. 2010. The Fowler syndrome-associated protein FLVCR2 is an importer of heme. Mol. Cell. Biol. 30:225318–24
    [Google Scholar]
30. 30.

    Enns CA, Jue S, Zhang A-S. 2021. Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice. Blood 138:6486–99
    [Google Scholar]
31. 31.

    Fillebeen C, Gkouvatsos K, Fragoso G, Calvé A, Garcia-Santos D et al. 2015. Mice are poor heme absorbers and do not require intestinal Hmox1 for dietary heme iron assimilation. Haematologica 100:9e334–37
    [Google Scholar]
32. 32.

    Fiorito V, Allocco AL, Petrillo S, Gazzano E, Torretta S et al. 2021. The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation. Cell Rep 35:11109252
    [Google Scholar]
33. 33.

    Fujimaki M, Furuya N, Saiki S, Amo T, Imamichi Y, Hattori N. 2019. Iron supply via NCOA4-mediated ferritin degradation maintains mitochondrial functions. Mol. Cell. Biol. 39:14e00010–19
    [Google Scholar]
34. 34.

    Galmozzi A, Kok BP, Kim AS, Montenegro-Burke JR, Lee JY et al. 2019. PGRMC2 is an intracellular haem chaperone critical for adipocyte function. Nature 576:7785138–42
    [Google Scholar]
35. 35.

    Gao J, Zhou Q, Wu D, Chen L 2021. Mitochondrial iron metabolism and its role in diseases. Clin. Chim. Acta 513:6–12
    [Google Scholar]
36. 36.

    Gburek J, Verroust PJ, Willnow TE, Fyfe JC, Nowacki W et al. 2002. Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin. J. Am. Soc. Nephrol. 13:2423–30
    [Google Scholar]
37. 37.

    Gräsbeck R, Kouvonen I, Lundberg M, Tenhunen R. 1979. An intestinal receptor for heme. Scand. J. Haematol. 23:15–9
    [Google Scholar]
38. 38.

    Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M et al. 2009. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat. Genet. 41:6651–53
    [Google Scholar]
39. 39.

    Hamza I, Dailey HA. 2012. One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans. Biochim. Biophys. Acta Mol. Cell Res. 1823:91617–32
    [Google Scholar]
40. 40.

    Hanna DA, Martinez-Guzman O, Reddi AR. 2017. Heme gazing: illuminating eukaryotic heme trafficking, dynamics, and signaling with fluorescent heme sensors. Biochemistry 56:131815–23
    [Google Scholar]
41. 41.

    Huynh N, Ou Q, Cox P, Lill R, King-Jones K. 2019. Glycogen branching enzyme controls cellular iron homeostasis via Iron Regulatory Protein 1 and mitoNEET. Nat. Commun. 10:5463
    [Google Scholar]
42. 42.

    Ijssennagger N, Belzer C, Hooiveld GJ, Dekker J, van Mil SWC et al. 2015. Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon. PNAS 112:3210038–43
    [Google Scholar]
43. 43.

    Jennifer B, Berg V, Modak M, Puck A, Seyerl-Jiresch M et al. 2020. Transferrin receptor 1 is a cellular receptor for human heme-albumin. Commun. Biol. 3:1621
    [Google Scholar]
44. 44.

    Jiang L, Wang J, Wang K, Wang H, Wu Q et al. 2021. RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation. Blood 138:8689–705
    [Google Scholar]
45. 45.

    Jonker JW, Buitelaar M, Wagenaar E, van der Valk MA, Scheffer GL et al. 2002. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. PNAS 99:2415649–54
    [Google Scholar]
46. 46.

    Kafina MD, Paw BH. 2017. Intracellular iron and heme trafficking and metabolism in developing erythroblasts. Metallomics 9:91193–203
    [Google Scholar]
47. 47.

    Kalailingam P, Wang KQ, Toh XR, Nguyen TQ, Chandrakanthan M et al. 2020. Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome. J. Clin. Investig. 130:84081–93
    [Google Scholar]
48. 48.

    Kalisch-Smith JI, Ved N, Szumska D, Munro J, Troup M et al. 2021. Maternal iron deficiency perturbs embryonic cardiovascular development in mice. Nat. Commun. 12:13447
    [Google Scholar]
49. 49.

    Kämmerer L, Mohammad G, Wolna M, Robbins PA, Lakhal-Littleton S. 2020. Fetal liver hepcidin secures iron stores in utero. Blood 136:131549–57
    [Google Scholar]
50. 50.

    Khan AA, Quigley JG. 2013. Heme and FLVCR-related transporter families SLC48 and SLC49. Mol. Aspects Med. 34:2–3669–82
    [Google Scholar]
51. 51.

    Kikuchi G, Yoshida T, Noguchi M. 2005. Heme oxygenase and heme degradation. Biochem. Biophys. Res. Commun. 338:1558–67
    [Google Scholar]
52. 52.

    Kim P. 2017. Peroxisome biogenesis: a union between two organelles. Curr. Biol. 27:7R271–74
    [Google Scholar]
53. 53.

    Kiss K, Brozik A, Kucsma N, Toth A, Gera M et al. 2012. Shifting the paradigm: The putative mitochondrial protein ABCB6 resides in the lysosomes of cells and in the plasma membrane of erythrocytes. PLOS ONE 7:5e37378
    [Google Scholar]
54. 54.

    Koleini N, Shapiro JS, Geier J, Ardehali H. 2021. Ironing out mechanisms of iron homeostasis and disorders of iron deficiency. J. Clin. Investig. 131:11e148671
    [Google Scholar]
55. 55.

    Korolnek T, Hamza I. 2014. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front. Pharmacol. 5:126
    [Google Scholar]
56. 56.

    Korolnek T, Zhang J, Beardsley S, Scheffer GL, Hamza I. 2014. Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell Metab 19:61008–19
    [Google Scholar]
57. 57.

    Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J et al. 2006. Identification of a mammalian mitochondrial porphyrin transporter. Nature 443:7111586–89
    [Google Scholar]
58. 58.

    Kwan STC, Kezer CA, Helfrich KK, Saini N, Huebner SM et al. 2020. Maternal iron nutriture modulates placental development in a rat model of fetal alcohol spectrum disorder. Alcohol 84:57–66
    [Google Scholar]
59. 59.

    Lakhal-Littleton S. 2021. Advances in understanding the crosstalk between mother and fetus on iron utilization. Semin. Hematol. 58:3153–60
    [Google Scholar]
60. 60.

    Ledesma-Colunga MG, Baschant U, Fiedler IAK, Busse B, Hofbauer LC et al. 2020. Disruption of the hepcidin/ferroportin regulatory circuitry causes low axial bone mass in mice. Bone 137:115400
    [Google Scholar]
61. 61.

    Li G, Zhang H, Wu J, Wang A, Yang F et al. 2020. Hepcidin deficiency causes bone loss through interfering with the canonical Wnt/β-catenin pathway via Forkhead box O3a. J. Orthop. Translat. 23:67–76
    [Google Scholar]
62. 62.

    Li J, Pan X, Pan G, Song Z, He Y et al. 2020. Transferrin receptor 1 regulates thermogenic capacity and cell fate in brown/beige adipocytes. Adv. Sci. (Weinh.) 7:121903366
    [Google Scholar]
63. 63.

    Li X, Lozovatsky L, Sukumaran A, Gonzalez L, Jain A et al. 2020. NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss. Blood 136:232691–702
    [Google Scholar]
64. 64.

    Li Y, Ivica NA, Dong T, Papageorgiou DP, He Y et al. 2020. MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme. Nat. Commun. 11:14837
    [Google Scholar]
65. 65.

    Liang R, Menon V, Qiu J, Arif T, Renuse S et al. 2021. Mitochondrial localization and moderated activity are key to murine erythroid enucleation. Blood Adv 5:102490–504
    [Google Scholar]
66. 66.

    Lill R, Kispal G. 2001. Mitochondrial ABC transporters. Res. Microbiol. 152:3–4331–40
    [Google Scholar]
67. 67.

    Lim PJ, Duarte TL, Arezes J, Garcia-Santos D, Hamdi A et al. 2019. Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat. Metab. 1:5519–31
    [Google Scholar]
68. 68.

    Liu G, Sil D, Maio N, Tong W-H, Bollinger JM et al. 2020. Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase. Nat. Commun. 11:16310
    [Google Scholar]
69. 69.

    Lunetti P, Damiano F, De Benedetto G, Siculella L, Pennetta A et al. 2016. Characterization of human and yeast mitochondrial glycine carriers with implications for heme biosynthesis and anemia. J. Biol. Chem. 291:3819746–59
    [Google Scholar]
70. 70.

    Ma S, Dubin AE, Zhang Y, Mousavi SAR, Wang Y et al. 2021. A role of PIEZO1 in iron metabolism in mice and humans. Cell 184:4969–82.e13
    [Google Scholar]
71. 71.

    Maio N, Kim KS, Holmes-Hampton G, Singh A, Rouault TA. 2019. Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally defined molecular complex required for heme biosynthesis. Haematologica 104:91756–67
    [Google Scholar]
72. 72.

    Manolaridis I, Jackson SM, Taylor NMI, Kowal J, Stahlberg H, Locher KP. 2018. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature 563:7731426–30
    [Google Scholar]
73. 73.

    Martinez-Guzman O, Willoughby MM, Saini A, Dietz JV, Bohovych I et al. 2020. Mitochondrial-nuclear heme trafficking in budding yeast is regulated by GTPases that control mitochondrial dynamics and ER contact sites. J. Cell Sci. 133:10jcs237917
    [Google Scholar]
74. 74.

    Matz JM, Drepper B, Blum TB, van Genderen E, Burrell A et al. 2020. A lipocalin mediates unidirectional heme biomineralization in malaria parasites. PNAS 117:2816546–56
    [Google Scholar]
75. 75.

    McMahon M, Ding S, Acosta-Jimenez LP, Frangova TG, Henderson CJ, Wolf CR. 2018. Measuring in vivo responses to endogenous and exogenous oxidative stress using a novel haem oxygenase 1 reporter mouse. J. Physiol. 596:1105–27
    [Google Scholar]
76. 76.

    Medina MV, Sapochnik D, Garcia Solá M, Coso O 2020. Regulation of the expression of heme oxygenase-1: signal transduction, gene promoter activation, and beyond. Antioxid Redox Signal 32:141033–44
    [Google Scholar]
77. 77.

    Medlock AE, Shiferaw MT, Marcero JR, Vashisht AA, Wohlschlegel JA et al. 2015. Identification of the mitochondrial heme metabolism complex. PLOS ONE 10:8e0135896
    [Google Scholar]
78. 78.

    Mercadante CJ, Prajapati M, Parmar JH, Conboy HL, Dash ME et al. 2019. Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess. Haematologica 104:4678–89
    [Google Scholar]
79. 79.

    Mleczko-Sanecka K, Silvestri L. 2021. Cell-type-specific insights into iron regulatory processes. Am. J. Hematol. 96:1110–27
    [Google Scholar]
80. 80.

    Montemiglio LC, Testi C, Ceci P, Falvo E, Pitea M et al. 2019. Cryo-EM structure of the human ferritin-transferrin receptor 1 complex. Nat. Commun. 10:11121
    [Google Scholar]
81. 81.

    Muckenthaler MU, Rivella S, Hentze MW, Galy B. 2017. A red carpet for iron metabolism. Cell 168:3344–61
    [Google Scholar]
82. 82.

    Mukherjee C, Kling T, Russo B, Miebach K, Kess E et al. 2020. Oligodendrocytes provide antioxidant defense function for neurons by secreting ferritin heavy chain. Cell Metab 32:2259–72.e10
    [Google Scholar]
83. 83.

    Müller S, Sindikubwabo F, Cañeque T, Lafon A, Versini A et al. 2020. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat. Chem. 12:10929–38
    [Google Scholar]
84. 84.

    Munakata H, Sun J-Y, Yoshida K, Nakatani T, Honda E et al. 2004. Role of the heme regulatory motif in the heme-mediated inhibition of mitochondrial import of 5-aminolevulinate synthase. J. Biochem. 136:2233–38
    [Google Scholar]
85. 85.

    Murata Y, Yoshida M, Sakamoto N, Morimoto S, Watanabe T, Namba K. 2021. Iron uptake mediated by the plant-derived chelator nicotianamine in the small intestine. J. Biol. Chem. 296:100195
    [Google Scholar]
86. 86.

    Neuspiel M, Schauss AC, Braschi E, Zunino R, Rippstein P et al. 2008. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr. Biol. 18:2102–8
    [Google Scholar]
87. 87.

    Nilsson R, Schultz IJ, Pierce EL, Soltis KA, Naranuntarat A et al. 2009. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab 10:2119–30
    [Google Scholar]
88. 88.

    O'Callaghan KM, Ayllon V, O'Keeffe J, Wang Y, Cox OT et al. 2010. 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. J. Biol. Chem. 285:1381–91
    [Google Scholar]
89. 89.

    O'Keeffe R, Latunde-Dada GO, Chen Y-L, Kong XL, Cilibrizzi A, Hider RC. 2021. Glutathione and the intracellular labile heme pool. Biometals 34:2221–28
    [Google Scholar]
90. 90.

    Ouled-Haddou H, Messaoudi K, Demont Y, Lopes Dos Santos R, Carola C et al. 2020. A new role of glutathione peroxidase 4 during human erythroblast enucleation. Blood Adv 4:225666–80
    [Google Scholar]
91. 91.

    Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H et al. 1996. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol. 16:116083–95
    [Google Scholar]
92. 92.

    Pan Y, Ren Z, Gao S, Shen J, Wang L et al. 2020. Structural basis of ion transport and inhibition in ferroportin. Nat. Commun. 11:5686
    [Google Scholar]
93. 93.

    Parrow NL, Li Y, Feola M, Guerra A, Casu C et al. 2019. Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis. Blood 134:171373–84
    [Google Scholar]
94. 94.

    Pasricha S-R, Tye-Din J, Muckenthaler MU, Swinkels DW. 2021. Iron deficiency. Lancet 397:10270233–48
    [Google Scholar]
95. 95.

    Patel SJ, Protchenko O, Shakoury-Elizeh M, Baratz E, Jadhav S, Philpott CC. 2021. The iron chaperone and nucleic acid-binding activities of poly(rC)-binding protein 1 are separable and independently essential. PNAS 118:25e2104666118
    [Google Scholar]
96. 96.

    Pek RH, Yuan X, Rietzschel N, Zhang J, Jackson L et al. 2019. Hemozoin produced by mammals confers heme tolerance. eLife 8:e49503
    [Google Scholar]
97. 97.

    Perally S, Lacourse EJ, Campbell AM, Brophy PM. 2008. Heme transport and detoxification in nematodes: subproteomics evidence of differential role of glutathione transferases. J. Proteome Res. 7:104557–65
    [Google Scholar]
98. 98.

    Philip M, Funkhouser SA, Chiu EY, Phelps SR, Delrow JJ et al. 2015. Heme exporter FLVCR is required for T cell development and peripheral survival. J. Immunol. 194:41677–85
    [Google Scholar]
99. 99.

    Piel RB, Dailey HA, Medlock AE. 2019. The mitochondrial heme metabolon: insights into the complex(ity) of heme synthesis and distribution. Mol. Genet. Metab. 128:3198–203
    [Google Scholar]
100. 100.

     Piel RB, Shiferaw MT, Vashisht AA, Marcero JR, Praissman JL et al. 2016. A novel role for progesterone receptor membrane component 1 (PGRMC1): a partner and regulator of ferrochelatase. Biochemistry 55:375204–17
     [Google Scholar]
101. 101.

     Ponka P, Sheftel AD, English AM, Scott Bohle D, Garcia-Santos D 2017. Do mammalian cells really need to export and import heme?. Trends Biochem. Sci. 42:5395–406
     [Google Scholar]
102. 102.

     Pradhan P, Vijayan V, Gueler F, Immenschuh S. 2020. Interplay of heme with macrophages in homeostasis and inflammation. Int. J. Mol. Sci. 21:3E740
     [Google Scholar]
103. 103.

     Prajapati M, Conboy HL, Hojyo S, Fukada T, Budnik B, Bartnikas TB. 2021. Biliary excretion of excess iron in mice requires hepatocyte iron import by Slc39a14. J. Biol. Chem. 297:1100835
     [Google Scholar]
104. 104.

     Protchenko O, Baratz E, Jadhav S, Li F, Shakoury-Elizeh M et al. 2021. Iron chaperone poly rC binding protein 1 protects mouse liver from lipid peroxidation and steatosis. Hepatology 73:31176–93
     [Google Scholar]
105. 105.

     Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S et al. 2006. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127:5917–28
     [Google Scholar]
106. 106.

     Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM et al. 2004. Identification of a human heme exporter that is essential for erythropoiesis. Cell 118:6757–66
     [Google Scholar]
107. 107.

     Rajagopal A, Rao AU, Amigo J, Tian M, Upadhyay SK et al. 2008. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453:71981127–31
     [Google Scholar]
108. 108.

     Rakvács Z, Kucsma N, Gera M, Igriczi B, Kiss K et al. 2019. The human ABCB6 protein is the functional homologue of HMT-1 proteins mediating cadmium detoxification. Cell. Mol. Life Sci. 76:204131–44
     [Google Scholar]
109. 109.

     Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S et al. 2019. Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling. Nat. Metab. 1:1111–24
     [Google Scholar]
110. 110.

     Rondelli CM, Perfetto M, Danoff A, Bergonia H, Gillis S et al. 2021. The ubiquitous mitochondrial protein unfoldase CLPX regulates erythroid heme synthesis by control of iron utilization and heme synthesis enzyme activation and turnover. J. Biol. Chem. 297:2100972
     [Google Scholar]
111. 111.

     Sangkhae V, Fisher AL, Chua KJ, Ruchala P, Ganz T, Nemeth E. 2020. Maternal hepcidin determines embryo iron homeostasis in mice. Blood 136:192206–16
     [Google Scholar]
112. 112.

     Sangkhae V, Fisher AL, Wong S, Koenig MD, Tussing-Humphreys L et al. 2020. Effects of maternal iron status on placental and fetal iron homeostasis. J. Clin. Investig. 130:2625–40
     [Google Scholar]
113. 113.

     Santana-Codina N, Gableske S, Quiles del Rey M, Małachowska B, Jedrychowski MP et al. 2019. NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms. Haematologica 104:71342–54
     [Google Scholar]
114. 114.

     Santander N, Lizama CO, Meky E, McKinsey GL, Jung B et al. 2020. Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier. J. Clin. Investig. 130:84055–68
     [Google Scholar]
115. 115.

     Sarkar A, Carter EL, Harland JB, Speelman AL, Lehnert N, Ragsdale SW. 2021. Ferric heme as a CO/NO sensor in the nuclear receptor Rev-Erbβ by coupling gas binding to electron transfer. PNAS 118:3e2016717118
     [Google Scholar]
116. 116.

     Schubert ML. 2017. Physiologic, pathophysiologic, and pharmacologic regulation of gastric acid secretion. Curr. Opin. Gastroenterol. 33:6430–38
     [Google Scholar]
117. 117.

     Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic MT et al. 2019. Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J. Clin. Investig. 129:1336–48
     [Google Scholar]
118. 118.

     Scorrano L, De Matteis MA, Emr S, Giordano F, Hajnóczky G et al. 2019. Coming together to define membrane contact sites. Nat. Commun. 10:11287
     [Google Scholar]
119. 119.

     Severance S, Hamza I. 2009. Trafficking of heme and porphyrins in metazoa. Chem. Rev. 109:104596–616
     [Google Scholar]
120. 120.

     Severance S, Rajagopal A, Rao AU, Cerqueira GC, Mitreva M et al. 2010. Genome-wide analysis reveals novel genes essential for heme homeostasis in Caenorhabditis elegans. PLOS Genet 6:7e1001044
     [Google Scholar]
121. 121.

     Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K et al. 2005. Identification of an intestinal heme transporter. Cell 122:5789–801
     [Google Scholar]
122. 122.

     Sinclair J, Hamza I. 2015. Lessons from bloodless worms: heme homeostasis in C. elegans. Biometals 28:3481–89
     [Google Scholar]
123. 123.

     Smith A, McCulloh RJ. 2015. Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front. Physiol. 6:187
     [Google Scholar]
124. 124.

     Sobh A, Loguinov A, Zhou J, Jenkitkasemwong S, Zeidan R et al. 2020. Genetic screens reveal CCDC115 as a modulator of erythroid iron and heme trafficking. Am. J. Hematol. 95:91085–98
     [Google Scholar]
125. 125.

     Song G, Zhang S, Tian M, Zhang L, Guo R et al. 2021. Molecular insights into the human ABCB6 transporter. Cell Discov 7:155
     [Google Scholar]
126. 126.

     Soubannier V, McLelland G-L, Zunino R, Braschi E, Rippstein P et al. 2012. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22:2135–41
     [Google Scholar]
127. 127.

     Speich C, Wegmüller R, Brittenham GM, Zeder C, Cercamondi CI et al. 2021. Measurement of long-term iron absorption and loss during iron supplementation using a stable isotope of iron (⁵⁷Fe). Br. J. Haematol. 192:1179–89
     [Google Scholar]
128. 128.

     Srole DN, Ganz T. 2021. Erythroferrone structure, function, and physiology: iron homeostasis and beyond. J. Cell. Physiol. 236:74888–901
     [Google Scholar]
129. 129.

     Swenson SA, Moore CM, Marcero JR, Medlock AE, Reddi AR, Khalimonchuk O. 2020. From synthesis to utilization: the ins and outs of mitochondrial heme. Cells 9:3E579
     [Google Scholar]
130. 130.

     Traeger L, Wiegand SB, Sauer AJ, Corman BHP, Peneyra KM et al. 2021. UBA6 and NDFIP1 regulate the degradation of ferroportin. Haematologica 107:2478–88
     [Google Scholar]
131. 131.

     Vincent SH, Muller-Eberhard U. 1985. A protein of the Z class of liver cytosolic proteins in the rat that preferentially binds heme. J. Biol. Chem. 260:2714521–28
     [Google Scholar]
132. 132.

     Wang C-Y, Xiao X, Bayer A, Xu Y, Dev S et al. 2019. Ablation of hepatocyte Smad1, Smad5, and Smad8 causes severe tissue iron loading and liver fibrosis in mice. Hepatology 70:61986–2002
     [Google Scholar]
133. 133.

     Warnatz H-J, Schmidt D, Manke T, Piccini I, Sultan M et al. 2011. The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. J. Biol. Chem. 286:2623521–32
     [Google Scholar]
134. 134.

     Watanabe Y, Ishimori K, Uchida T. 2017. Dual role of the active-center cysteine in human peroxiredoxin 1: peroxidase activity and heme binding. Biochem. Biophys. Res. Commun. 483:3930–35
     [Google Scholar]
135. 135.

     Weber RA, Yen FS, Nicholson SPV, Alwaseem H, Bayraktar EC et al. 2020. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol. Cell 77:3645–55.e7
     [Google Scholar]
136. 136.

     West A-R, Oates P-S. 2008. Mechanisms of heme iron absorption: current questions and controversies. World J. Gastroenterol. 14:264101–10
     [Google Scholar]
137. 137.

     White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK et al. 2013. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17:2261–70
     [Google Scholar]
138. 138.

     Wyllie JC, Kaufman N. 1982. An electron microscopic study of heme uptake by rat duodenum. Lab. Investig. 47:5471–76
     [Google Scholar]
139. 139.

     Xiao X, Dev S, Canali S, Bayer A, Xu Y et al. 2020. Endothelial bone morphogenetic protein 2 (Bmp2) knockout exacerbates hemochromatosis in homeostatic iron regulator (Hfe) knockout mice but not Bmp6 knockout mice. Hepatology 72:2642–55
     [Google Scholar]
140. 140.

     Yachie A. 2021. Heme oxygenase-1 deficiency and oxidative stress: a review of 9 independent human cases and animal models. Int. J. Mol. Sci. 22:41514
     [Google Scholar]
141. 141.

     Yambire KF, Rostosky C, Watanabe T, Pacheu-Grau D, Torres-Odio S et al. 2019. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife 8:e51031
     [Google Scholar]
142. 142.

     Yanatori I, Richardson DR, Dhekne HS, Toyokuni S, Kishi F. 2021. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood 138:161490–503
     [Google Scholar]
143. 143.

     Yang Z, Philips JD, Doty RT, Giraudi P, Ostrow JD et al. 2010. Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin. J. Biol. Chem. 285:3728874–82
     [Google Scholar]
144. 144.

     Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B et al. 2014. TMEM14C is required for erythroid mitochondrial heme metabolism. J. Clin. Investig. 124:104294–304
     [Google Scholar]
145. 145.

     Yu Y, Jiang L, Wang H, Shen Z, Cheng Q et al. 2020. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 136:6726–39
     [Google Scholar]
146. 146.

     Yuan X, Protchenko O, Philpott CC, Hamza I. 2012. Topologically conserved residues direct heme transport in HRG-1-related proteins. J. Biol. Chem. 287:74914–24
     [Google Scholar]
147. 147.

     Yuan X, Rietzschel N, Kwon H, Walter Nuno AB, Hanna DA et al. 2016. Regulation of intracellular heme trafficking revealed by subcellular reporters. PNAS 113:35E5144–52
     [Google Scholar]
148. 148.

     Zhang D-L, Wu J, Shah BN, Greutélaers KC, Ghosh MC et al. 2018. Erythrocytic ferroportin reduces intracellular iron accumulation, hemolysis, and malaria risk. Science 359:63831520–23
     [Google Scholar]
149. 149.

     Zhang Z, Funcke J-B, Zi Z, Zhao S, Straub LG et al. 2021. Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity. Cell Metab 33:81624–39.e9
     [Google Scholar]
150. 150.

     Zheng J, Shan Y, Lambrecht RW, Donohue SE, Bonkovsky HL. 2008. Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin. Mol. Cell. Biochem. 319:1–2153–61
     [Google Scholar]