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Title: Hemozoin produced by mammals confers heme tolerance

Abstract

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.

Authors:
ORCiD logo [1]; ORCiD logo [1];  [1];  [1];  [2];  [3];  [1];  [4];  [4]; ORCiD logo [5];  [6];  [7];  [6];  [8];  [2];  [4]; ORCiD logo [1]
  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
  2. Department of Medicine, University of Utah School of Medicine, Salt Lake City, United States
  3. Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan, Tsukuba Research Center for Energy Materials Science, University of Tsukaba, Tsukaba, Japan
  4. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
  5. RIKEN SPring-8 Center, Sayo, Hyogo, Japan
  6. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
  7. NHGRI Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
  8. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, United States
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1567862
Alternate Identifier(s):
OSTI ID: 1567864
Grant/Contract Number:  
AC02-06CH11357; 2017A0074
Resource Type:
Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Name: eLife Journal Volume: 8; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
English

Citation Formats

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., and Hamza, Iqbal. Hemozoin produced by mammals confers heme tolerance. United States: N. p., 2019. Web. doi:10.7554/eLife.49503.
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. Hemozoin produced by mammals confers heme tolerance. United States. doi:10.7554/eLife.49503.
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., and Hamza, Iqbal. Tue . "Hemozoin produced by mammals confers heme tolerance". United States. doi:10.7554/eLife.49503.
@article{osti_1567862,
title = {Hemozoin produced by mammals confers heme tolerance},
author = {Pek, Rini H. and Yuan, Xiaojing and Rietzschel, Nicole and Zhang, Jianbing and Jackson, Laurie and Nishibori, Eiji and Ribeiro, Ana and Simmons, William and Jagadeesh, Jaya and Sugimoto, Hiroshi and Alam, Md Zahidul and Garrett, Lisa and Haldar, Malay and Ralle, Martina and Phillips, John D. and Bodine, David M. and Hamza, Iqbal},
abstractNote = {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.},
doi = {10.7554/eLife.49503},
journal = {eLife},
number = ,
volume = 8,
place = {United States},
year = {2019},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.7554/eLife.49503

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