@article{3e5747ad8ea04b878c166c41749be9a4,
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.",
author = "Pek, {Rini H.} and Xiaojing Yuan and Nicole Rietzschel and Jianbing Zhang and Laurie Jackson and Eiji Nishibori and Ana Ribeiro and William Simmons and Jaya Jagadeesh and Hiroshi Sugimoto and Alam, {Md Zahidul} and Lisa Garrett and Malay Haldar and Martina Ralle and Phillips, {John D.} and Bodine, {David M.} and Iqbal Hamza",
note = "Funding Information: We thank Hector Bergonia for help with the heme/UPLC measurements; Stacie Anderson and Martha Kirby for assistance with flow cytometry analyses; Edward Case for59Fe calibration and counting; Hidetaka Kasai and Shogo Kawaguchi for x-ray powder diffraction data collection; Paul Sigala for providing Plasmodium falciparum hemozoin; Si Chen at the Advanced Photon Source for assistance with the XFM experiments; and Susumu Tonegawa and Tracey Rouault for the HMOX1 mice. This work was supported by funding from the National Institutes of Health DK85035 and ES025661 (IH); T32 GM080201 (RP); the Utah Center for Iron and Heme Disorders was supported by funding from DK110858 (JP); and the Intramural Program of the National Human Genome Research Institute (LJG, DB). We acknowledge use of the Advanced Photon Source at Argonne National Laboratory, supported by the Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. The synchrotron experiments were performed at SPring-8 BL02B2 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) as a Partner User (Proposal No. 2017A0074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank Hector Bergonia for help with the heme/UPLC measurements; Stacie Anderson and Martha Kirby for assistance with flow cytometry analyses; Edward Case for 59Fe calibration and counting; Hidetaka Kasai and Shogo Kawaguchi for x-ray powder diffraction data collection; Paul Sigala for providing Plasmodium falciparum hemozoin; Si Chen at the Advanced Photon Source for assistance with the XFM experiments; and Susumu Tonegawa and Tracey Rouault for the HMOX1 mice. This work was supported by funding from the National Institutes of Health DK85035 and ES025661 (IH); T32 GM080201 (RP); the Utah Center for Iron and Heme Disorders was supported by funding from DK110858 (JP); and the Intramural Program of the National Human Genome Research Institute (LJG, DB). We acknowledge use of the Advanced Photon Source at Argonne National Laboratory, supported by the Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357. The synchrotron experiments were performed at SPring-8 BL02B2 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) as a Partner User (Proposal No. 2017A0074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019, eLife Sciences Publications Ltd. All rights reserved.",
year = "2019",
month = oct,
doi = "10.7554/eLife.49503",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}