A role of PIEZO1 in iron metabolism in mice and humans

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.

Automated summary

Iron overload can cause progressive organ damage and is associated with genetic factors affecting iron homeostasis. Certain individuals with hereditary disorders may develop iron overload, and some GOF PIEZO1 alleles are linked to iron imbalance. The study demonstrates the key role of PIEZO1 in macrophage phagocytic activity and iron metabolism, with a particular GOF PIEZO1 allele showing a strong association with increased plasma iron levels in individuals of African descent.