PT  - JOURNAL ARTICLE
AU  - Rini H. Pek
AU  - Xiaojing Yuan
AU  - Nicole Rietzschel
AU  - Jianbing Zhang
AU  - Laurie K. Jackson
AU  - Eiji Nishibori
AU  - Ana Ribeiro
AU  - William R. Simmons
AU  - Jaya Jagadeesh
AU  - Hiroshi Sugimoto
AU  - Md Zahidul Alam
AU  - Lisa J. Garrett
AU  - Malay Haldar
AU  - Martina Ralle
AU  - John Phillips
AU  - David Bodine
AU  - Iqbal Hamza
TI  - Hemozoin produced by mammals confers heme tolerance
AID  - 10.1101/629725
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 629725
4099  - http://biorxiv.org/content/early/2019/05/16/629725.short
4100  - http://biorxiv.org/content/early/2019/05/16/629725.full
AB  - 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 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 polymerizing them into crystalline hemozoin, which heretofore has only been found in blood-feeding parasites. HRG1 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 haploinsufficiency of HMOX1 combined with HRG1 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.