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 ^[7]; Haldar, Malay ^[6]; Ralle, Martina ^[8]; Phillips, John D. ^[2]; Bodine, David M. ^[4];

^[1]

Department of Animal and Avian Sciences, University of Maryland, College Park, United States, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, United States
Department of Medicine, University of Utah School of Medicine, Salt Lake City, United States
Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan, Tsukuba Research Center for Energy Materials Science, University of Tsukaba, Tsukaba, Japan
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
RIKEN SPring-8 Center, Sayo, Hyogo, Japan
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
NHGRI Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, 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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Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); 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

OSTI ID:: 1567862

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

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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