@article{976b0747160948a0b8870e9808368668,
title = "A role of PIEZO1 in iron metabolism in mice and humans",
abstract = "Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%–5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.",
keywords = "African American, Ion channel, PIEZO1, erythropoiesis, human genetics, iron metabolism, macrophage, mechanotransduction, phagocytosis",
author = "Shang Ma and Dubin, {Adrienne E.} and Yunxiao Zhang and Mousavi, {Seyed Ali Reza} and Yu Wang and Coombs, {Adam M.} and Meaghan Loud and Immacolata Andolfo and Ardem Patapoutian",
note = "Funding Information: We thank Adrienne Dubin, Tomas Ganz, Rose Hill, and Kara Marshall for critical reading of the manuscript. We thank Roberto Aiolfi from Ruggeri lab at The Scripps Research Institute (TSRI) for sharing ProCyte equipment. We also thank Achille Iolascon and Roberta Russo for discussions on experimental design. This work was supported by NIH grants R35 NS105067 and R01 DE022358 to A.P. S.M. was supported by a Calibr-GHDDI Gates postdoctoral fellowship. A.P. is an investigator of the Howard Hughes Medical Institute . Funding Information: We thank Adrienne Dubin, Tomas Ganz, Rose Hill, and Kara Marshall for critical reading of the manuscript. We thank Roberto Aiolfi from Ruggeri lab at The Scripps Research Institute (TSRI) for sharing ProCyte equipment. We also thank Achille Iolascon and Roberta Russo for discussions on experimental design. This work was supported by NIH grants R35 NS105067 and R01 DE022358 to A.P. S.M. was supported by a Calibr-GHDDI Gates postdoctoral fellowship. A.P. is an investigator of the Howard Hughes Medical Institute. A.P. and S.M. designed experiments and wrote the paper. S.M. performed all mouse experiments and human blood measurements. A.E.D. performed electrophysiology experiments. Y.Z. Y.W. and S.M. performed and analyzed cytometry experiments. S.A.R.M. and S.M. did immunocytochemistry staining and analysis. A.M.C. performed in situ hybridization. S.A.R.M. and S.M. genotyped human samples. M.L. and A.M.C. performed mouse genotyping. I.A. contributed by discussing experimental details. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = feb,
day = "18",
doi = "10.1016/j.cell.2021.01.024",
language = "English (US)",
volume = "184",
pages = "969--982.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}