Hemozoin produced by mammals confers heme tolerance

Pek, Rini H.; Yuan, Xiaojing; Rietzschel, Nicole; Zhang, Jianbing; Jackson, Laurie; Nishibori, Eiji; Ribeiro, Ana; Simmons, William; Jagadeesh, Jaya; Sugimoto, Hiroshi; Alam, Md Zahidul; Garrett, Lisa; Haldar, Malay; Ralle, Martina; Phillips, John D.; Bodine, David M.; Hamza, Iqbal

doi:10.7554/eLife.49503

Title: Hemozoin produced by mammals confers heme tolerance

Journal Article · 01 October 2019 · eLife

DOI: https://doi.org/10.7554/eLife.49503 · OSTI ID:1567862

^[1];

^[1]; Rietzschel, Nicole ^[1]; Zhang, Jianbing ^[1]; Jackson, Laurie ^[2]; Nishibori, Eiji ^[3]; Ribeiro, Ana ^[1]; Simmons, William ^[4]; Jagadeesh, Jaya ^[4];

^[5]; Alam, Md Zahidul ^[6]; Garrett, Lisa ^[4]; Haldar, Malay ^[6]; Ralle, Martina ^[7]; Phillips, John D. ^[2]; Bodine, David M. ^[4];

^[1]

Univ. of Maryland, College Park, MD (United States)
Univ. of Utah School of Medicine, Salt Lake City, UT (United States)
Univ. of Tsukuba (Japan)
National Inst. of Health (NIH), Bethesda, MD (United States)
RIKEN SPring-8 Center, Hyogo (Japan)
Univ. of Pennsylvania, Philadelphia, PA (United States)
Oregon Health and Science Univ., Portland, OR (United States)

Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by crystallizing them into hemozoin, which heretofore has only been found in blood-feeding organisms. SLC48A1 deficiency results in impaired erythroid maturation and an inability to systemically respond to iron deficiency. Complete heme tolerance requires a fully-operational heme degradation pathway as haplo insufficiency of HMOX1 combined with SLC48A1 inactivation causes perinatal lethality demonstrating synthetic lethal interactions between heme transport and degradation. Our studies establish the formation of hemozoin by mammals as a previously unsuspected heme tolerance pathway.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Diabetes and Digestive and Kidney Diseases; National Inst. of Environmental Health Sciences; National Human Genome Research Inst.; Japan Synchrotron Radiation Research Inst.

Grant/Contract Number:: AC02-06CH11357; DK085035; ES025661; DK110858; 2017A0074; T32 GM080201

OSTI ID:: 1567862

Alternate ID(s):: OSTI ID: 1567864; OSTI ID: 1600787

Journal Information:: eLife, Vol. 8, Issue 2019; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 27 works

Citation information provided by
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References (73)

Macrophages and Systemic Iron Homeostasis Ganz, Tomas Journal of Innate Immunity, Vol. 4, Issue 5-6 https://doi.org/10.1159/000336423	journal	January 2012
The Molecular Biology of Human Iron Metabolism Winter, William E.; Bazydlo, Lindsay A. L.; Harris, Neil S. Laboratory Medicine, Vol. 45, Issue 2 https://doi.org/10.1309/LMF28S2GIMXNWHMM	journal	May 2014
HEMOGLOBIN METABOLISM IN THE MALARIA PARASITE PLASMODIUM FALCIPARUM Francis, Susan E.; Sullivan, David J.; Goldberg, and Daniel E. Annual Review of Microbiology, Vol. 51, Issue 1 https://doi.org/10.1146/annurev.micro.51.1.97	journal	October 1997
Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin Knutson, M. D.; Oukka, M.; Koss, L. M. Proceedings of the National Academy of Sciences, Vol. 102, Issue 5 https://doi.org/10.1073/pnas.0409409102	journal	January 2005
Heme-Mediated SPI-C Induction Promotes Monocyte Differentiation into Iron-Recycling Macrophages Haldar, Malay; Kohyama, Masako; So, Alex Yick-Lun Cell, Vol. 156, Issue 6 https://doi.org/10.1016/j.cell.2014.01.069	journal	March 2014
An iron-carboxylate bond links the heme units of malaria pigment. Slater, A. F.; Swiggard, W. J.; Orton, B. R. Proceedings of the National Academy of Sciences, Vol. 88, Issue 2 https://doi.org/10.1073/pnas.88.2.325	journal	January 1991
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization Nemeth, E. Science, Vol. 306, Issue 5704 https://doi.org/10.1126/science.1104742	journal	December 2004
Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling Perry, John M.; Harandi, Omid F.; Porayette, Prashanth Blood, Vol. 113, Issue 4 https://doi.org/10.1182/blood-2008-03-147892	journal	January 2009
The position of lysosomes within the cell determines their luminal pH Johnson, Danielle E.; Ostrowski, Philip; Jaumouillé, Valentin The Journal of Cell Biology, Vol. 212, Issue 6 https://doi.org/10.1083/jcb.201507112	journal	March 2016
Malarial hemozoin: From target to tool Coronado, Lorena M.; Nadovich, Christopher T.; Spadafora, Carmenza Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1840, Issue 6 https://doi.org/10.1016/j.bbagen.2014.02.009	journal	June 2014
Heme oxygenase-1 affords protection against noncerebral forms of severe malaria Seixas, Elsa; Gozzelino, Raffaella; Chora, Ângelo Proceedings of the National Academy of Sciences, Vol. 106, Issue 37 https://doi.org/10.1073/pnas.0903419106	journal	August 2009
Acidification of the Endocytic and Exocytic Pathways Mellman, Ira; Fuchs, Renate; Helenius, Ari Annual Review of Biochemistry, Vol. 55, Issue 1 https://doi.org/10.1146/annurev.bi.55.070186.003311	journal	June 1986
Duodenal mRNA expression of iron related genes in response to iron loading and iron deficiency in four strains of mice Dupic, F. Gut, Vol. 51, Issue 5 https://doi.org/10.1136/gut.51.5.648	journal	November 2002
BMP4 and Madh5 regulate the erythroid response to acute anemia Lenox, Laurie E.; Perry, John M.; Paulson, Robert F. Blood, Vol. 105, Issue 7 https://doi.org/10.1182/blood-2004-02-0703	journal	April 2005
Molecular insights into stress erythropoiesis Socolovsky, Merav Current Opinion in Hematology, Vol. 14, Issue 3 https://doi.org/10.1097/MOH.0b013e3280de2bf1	journal	January 2007
Demonstration of the exponential decay law using beer froth Leike, A. European Journal of Physics, Vol. 23, Issue 1 https://doi.org/10.1088/0143-0807/23/1/304	journal	December 2001
Lysosome Transport as a Function of Lysosome Diameter Bandyopadhyay, Debjyoti; Cyphersmith, Austin; Zapata, Jairo A. PLoS ONE, Vol. 9, Issue 1 https://doi.org/10.1371/journal.pone.0086847	journal	January 2014
Age-Related Reference Intervals of the Main Biochemical and Hematological Parameters in C57BL/6J, 129SV/EV and C3H/HeJ Mouse Strains Mazzaccara, Cristina; Labruna, Giuseppe; Cito, Gennaro PLoS ONE, Vol. 3, Issue 11 https://doi.org/10.1371/journal.pone.0003772	journal	November 2008
Heme Cytotoxicity and the Pathogenesis of Immune-Mediated Inflammatory Diseases Larsen, Rasmus; Gouveia, Zélia; Soares, Miguel P. Frontiers in Pharmacology, Vol. 3 https://doi.org/10.3389/fphar.2012.00077	journal	January 2012
An essential cell-autonomous role for hepcidin in cardiac iron homeostasis Lakhal-Littleton, Samira; Wolna, Magda; Chung, Yu Jin eLife, Vol. 5 https://doi.org/10.7554/eLife.19804	journal	November 2016
HRG1 Is Essential for Heme Transport from the Phagolysosome of Macrophages during Erythrophagocytosis White, Carine; Yuan, Xiaojing; Schmidt, Paul J. Cell Metabolism, Vol. 17, Issue 2 https://doi.org/10.1016/j.cmet.2013.01.005	journal	February 2013
Haemoproteus and Schistosoma synthesize heme polymers similar to Plasmodium hemozoin and β-hematin Chen, Mary M.; Shi, Lirong; Sullivan, David J. Molecular and Biochemical Parasitology, Vol. 113, Issue 1 https://doi.org/10.1016/S0166-6851(00)00365-0	journal	March 2001
Reduced stress defense in heme oxygenase 1-deficient cells Poss, K. D.; Tonegawa, S. Proceedings of the National Academy of Sciences, Vol. 94, Issue 20 https://doi.org/10.1073/pnas.94.20.10925	journal	September 1997
MAPS : A set of software tools for analysis and visualization of 3D X-ray fluorescence data sets Vogt, S. Journal de Physique IV (Proceedings), Vol. 104 https://doi.org/10.1051/jp4:20030160	journal	March 2003
The Bionanoprobe: Synchrotron-Based Hard X-ray Fluorescence Microscopy for 2D/3D Trace Element Mapping Chen, Si; Paunesku, Tatjana; Yuan, Ye Microscopy Today, Vol. 23, Issue 3 https://doi.org/10.1017/S1551929515000401	journal	April 2015
Haemozoin formation Egan, Timothy J. Molecular and Biochemical Parasitology, Vol. 157, Issue 2 https://doi.org/10.1016/j.molbiopara.2007.11.005	journal	February 2008
Regulation of iron acquisition and iron distribution in mammals Ganz, Tomas; Nemeth, Elizabeta Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1763, Issue 7 https://doi.org/10.1016/j.bbamcr.2006.03.014	journal	July 2006
Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice Wang, Fudi; Paradkar, Prasad N.; Custodio, Angel O. Nature Genetics, Vol. 39, Issue 8 https://doi.org/10.1038/ng2059	journal	July 2007
The Mechanism of β-Hematin Formation in Acetate Solution. Parallels between Hemozoin Formation and Biomineralization Processes ^† Egan, Timothy J.; Mavuso, Winile W.; Ncokazi, Kanyile K. Biochemistry, Vol. 40, Issue 1 https://doi.org/10.1021/bi0013501	journal	January 2001
LAMP proteins are required for fusion of lysosomes with phagosomes Huynh, Kassidy K.; Eskelinen, Eeva-Liisa; Scott, Cameron C. The EMBO Journal, Vol. 26, Issue 2 https://doi.org/10.1038/sj.emboj.7601511	journal	January 2007
Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling Soe-Lin, Shan; Apte, Sameer S.; Mikhael, Marc R. Experimental Hematology, Vol. 38, Issue 8 https://doi.org/10.1016/j.exphem.2010.04.003	journal	August 2010
Improved methods for haemozoin quantification in tissues yield organ-and parasite-specific information in malaria-infected mice Deroost, Katrien; Lays, Natacha; Noppen, Sam Malaria Journal, Vol. 11, Issue 1 https://doi.org/10.1186/1475-2875-11-166	journal	January 2012
Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis Chen, K.; Liu, J.; Heck, S. Proceedings of the National Academy of Sciences, Vol. 106, Issue 41 https://doi.org/10.1073/pnas.0909296106	journal	September 2009
Subcellular Localization of Iron and Heme Metabolism Related Proteins at Early Stages of Erythrophagocytosis Delaby, Constance; Rondeau, Christiane; Pouzet, Cécile PLoS ONE, Vol. 7, Issue 7 https://doi.org/10.1371/journal.pone.0042199	journal	July 2012
A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis Keel, S. B.; Doty, R. T.; Yang, Z. Science, Vol. 319, Issue 5864 https://doi.org/10.1126/science.1151133	journal	February 2008
Effects of Weight-Bearing Activities on Bone Mineral Content and Density in Children and Adolescents: A Meta-Analysis: WEIGHT-BEARING ACTIVITIES ON BMC AND BMD IN CHILDREN AND ADOLESCENTS Behringer, Michael; Gruetzner, Sebastian; McCourt, Molly Journal of Bone and Mineral Research, Vol. 29, Issue 2 https://doi.org/10.1002/jbmr.2036	journal	January 2014
Heme and blood-feeding parasites: friends or foes? Toh, Shu; Glanfield, Amber; Gobert, Geoffrey N. Parasites & Vectors, Vol. 3, Issue 1 https://doi.org/10.1186/1756-3305-3-108	journal	January 2010
Measurement of Heme Concentration Sinclair, Peter R.; Gorman, Nadia; Jacobs, Judith M. Current Protocols in Toxicology, Vol. 00, Issue 1 https://doi.org/10.1002/0471140856.tx0803s00	journal	May 1999
The Role of the Four Stereoisomers of the Heme Fe–O Cyclic Dimer in the Crystalline Phase Behavior of Synthetic Hemozoin: Relevance to Native Hemozoin Crystallization Straasø, Tine; Kapishnikov, Sergey; Kato, Kenichi Crystal Growth & Design, Vol. 11, Issue 8 https://doi.org/10.1021/cg200410b	journal	August 2011
Recycling Iron in Normal and Pathological States Beaumont, Carole; Delaby, Constance Seminars in Hematology, Vol. 46, Issue 4 https://doi.org/10.1053/j.seminhematol.2009.06.004	journal	October 2009
Dysfunction of the heme recycling system in heme oxygenase 1–deficient mice: effects on macrophage viability and tissue iron distribution Kovtunovych, Gennadiy; Eckhaus, Michael A.; Ghosh, Manik C. Blood, Vol. 116, Issue 26 https://doi.org/10.1182/blood-2010-03-272138	journal	December 2010
Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins Rajagopal, Abbhirami; Rao, Anita U.; Amigo, Julio Nature, Vol. 453, Issue 7198 https://doi.org/10.1038/nature06934	journal	April 2008
Pyridine Hemochromagen Assay for Determining the Concentration of Heme in Purified Protein Solutions Barr, Ian; Guo, Feng BIO-PROTOCOL, Vol. 5, Issue 18 https://doi.org/10.21769/BioProtoc.1594	journal	January 2015
A physiological model to study iron recycling in macrophages Delaby, Constance; Pilard, Nathalie; Hetet, Gilles Experimental Cell Research, Vol. 310, Issue 1 https://doi.org/10.1016/j.yexcr.2005.07.002	journal	October 2005
From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis Klei, Thomas R. L.; Meinderts, Sanne M.; van den Berg, Timo K. Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.00073	journal	February 2017
Heme oxygenase 1 is required for mammalian iron reutilization Poss, K. D.; Tonegawa, S. Proceedings of the National Academy of Sciences, Vol. 94, Issue 20 https://doi.org/10.1073/pnas.94.20.10919	journal	September 1997
Heatmapper: web-enabled heat mapping for all Babicki, Sasha; Arndt, David; Marcu, Ana Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw419	journal	May 2016
Drug-induced immune hemolytic anemia Garratty, George Hematology, Vol. 2009, Issue 1 https://doi.org/10.1182/asheducation-2009.1.73	journal	January 2009
Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors Hempelmann, Ernst Parasitology Research, Vol. 100, Issue 4 https://doi.org/10.1007/s00436-006-0313-x	journal	November 2006
Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice Kovtunovych, Gennadiy; Ghosh, Manik C.; Ollivierre, Wade Blood, Vol. 124, Issue 9 https://doi.org/10.1182/blood-2014-02-554162	journal	August 2014
On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver Theurl, Igor; Hilgendorf, Ingo; Nairz, Manfred Nature Medicine, Vol. 22, Issue 8 https://doi.org/10.1038/nm.4146	journal	July 2016
Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection Orf, Katharine; Cunnington, Aubrey J. Frontiers in Microbiology, Vol. 6 https://doi.org/10.3389/fmicb.2015.00666	journal	June 2015
The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan Journal of Biological Chemistry, Vol. 291, Issue 32 https://doi.org/10.1074/jbc.M116.727248	journal	May 2016
Importance of Anemia and Transferrin Levels in the Regulation of Intestinal Iron Absorption in Hypotransferrinemic Mice Raja, K. B.; Pountney, D. J.; Simpson, R. J. Blood, Vol. 94, Issue 9 https://doi.org/10.1182/blood.V94.9.3185	journal	November 1999
Accurate structure factors and experimental charge densities from synchrotron X-ray powder diffraction data at SPring-8 Nishibori, Eiji; Sunaoshi, Eiji; Yoshida, Akihiro Acta Crystallographica Section A Foundations of Crystallography, Vol. 63, Issue 1 https://doi.org/10.1107/S0108767306047210	journal	December 2006
The Role of Oxidative Stress in Hemolytic Anemia Fibach, Eitan; Rachmilewitz, Eliezer Current Molecular Medicine, Vol. 8, Issue 7 https://doi.org/10.2174/156652408786241384	journal	November 2008
Hemolysis-induced lethality involves inflammasome activation by heme Dutra, Fabianno F.; Alves, Letícia S.; Rodrigues, Danielle Proceedings of the National Academy of Sciences, Vol. 111, Issue 39 https://doi.org/10.1073/pnas.1405023111	journal	September 2014
An update on iron physiology Muñoz, Manuel; Villar, Isabel; García-Erce, José Antonio World Journal of Gastroenterology, Vol. 15, Issue 37 https://doi.org/10.3748/wjg.15.4617	journal	January 2009
Innate inflammatory response to the malarial pigment hemozoin Shio, Marina T.; Kassa, Fikregabrail A.; Bellemare, Marie-Josée Microbes and Infection, Vol. 12, Issue 12-13 https://doi.org/10.1016/j.micinf.2010.07.001	journal	November 2010
Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages Knutson, Mitchell D.; Vafa, Mohammad R.; Haile, David J. Blood, Vol. 102, Issue 12 https://doi.org/10.1182/blood-2003-04-1250	journal	December 2003
Splenic red pulp macrophages are intrinsically superparamagnetic and contaminate magnetic cell isolates Franken, Lars; Klein, Marika; Spasova, Marina Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep12940	journal	August 2015
Hepcidin and iron homeostasis Ganz, Tomas; Nemeth, Elizabeta Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1823, Issue 9 https://doi.org/10.1016/j.bbamcr.2012.01.014	journal	September 2012
Molecular liaisons between erythropoiesis and iron metabolism Kautz, Leon; Nemeth, Elizabeta Blood, Vol. 124, Issue 4 https://doi.org/10.1182/blood-2014-05-516252	journal	July 2014
Phagocytosis of P. falciparum malarial pigment hemozoin by human monocytes inactivates monocyte protein kinase C Schwarzer, Evelin; Turrini, Franco; Giribaldi, Giuliana Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Vol. 1181, Issue 1 https://doi.org/10.1016/0925-4439(93)90089-J	journal	March 1993
Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo Soe-Lin, S.; Apte, S. S.; Andriopoulos, B. Proceedings of the National Academy of Sciences, Vol. 106, Issue 14 https://doi.org/10.1073/pnas.0900808106	journal	March 2009
The large Debye–Scherrer camera installed at SPring-8 BL02B2 for charge density studies Nishibori, E.; Takata, M.; Kato, K. Journal of Physics and Chemistry of Solids, Vol. 62, Issue 12 https://doi.org/10.1016/S0022-3697(01)00164-0	journal	December 2001
Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney Zhang, Jianbing; Chambers, Ian; Yun, Sijung PLOS Genetics, Vol. 14, Issue 9 https://doi.org/10.1371/journal.pgen.1007665	journal	September 2018
The Single Crystal X-ray Structure of β-Hematin DMSO Solvate Grown in the Presence of Chloroquine, a β-Hematin Growth-Rate Inhibitor Gildenhuys, Johandie; Roex, Tanya le; Egan, Timothy J. Journal of the American Chemical Society, Vol. 135, Issue 3 https://doi.org/10.1021/ja308741e	journal	January 2013
Importance of Anemia and Transferrin Levels in the Regulation of Intestinal Iron Absorption in Hypotransferrinemic Mice Raja, K. B.; Pountney, D. J.; Simpson, R. J. Blood, Vol. 94, Issue 9 https://doi.org/10.1182/blood.v94.9.3185.421a20_3185_3192	journal	November 1999
The large Debye–Scherrer camera installed at SPring-8 BL02B2 for charge density studies Nishibori, E.; Takata, M.; Kato, K. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, Vol. 467-468 https://doi.org/10.1016/s0168-9002(01)00639-8	journal	July 2001
Drug-induced immune hemolytic anemia Johnson, Susan T. Transfusion and Apheresis Science, Vol. 40, Issue 3 https://doi.org/10.1016/j.transci.2009.03.017	journal	June 2009
Drug-induced immune hemolytic anemia Salama, Abdulgabar Expert Opinion on Drug Safety, Vol. 8, Issue 1 https://doi.org/10.1517/14740330802577351	journal	December 2008
Both Nramp1 and Dmt1 Are Necessary for Efficient Macrophage Iron Recycling. Soe-Lin, Shan; Apte, Sameer S.; Mikhael, Marc R. Blood, Vol. 114, Issue 22 https://doi.org/10.1182/blood.v114.22.1994.1994	journal	November 2009

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