A role of PIEZO1 in iron metabolism in mice and humans

Iron is essential for cellular processes such as hemoglobin biosynthesis for oxygen transport. However, too much iron is toxic to organs ,thus, iron levels are tightly controlled by homeostatic processes. Iron homeostasis involves the action of multiple cell types, and key players include enterocytes, red blood cells (RBCs), macrophages, and hepatocytes. Many pathways involved in iron metabolism are emerging. However, the genetic factors that predispose people to iron overload are not well understood.

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. 

Scientists from Howard Hughes Medical Institute, show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. They further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, they 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.

Their strategy of selecting phenotypes in rare HX patients and elucidating mechanisms in transgenic mouse models has revealed an unexpected physiological relevance of mechanotransduction that goes beyond well-characterized mechanotransduction processes in physiology. Importantly, study of individuals carrying the E756del GOF PIEZO1 common allele translates our mechanistic understanding of mechanobiology into clinically relevant insights applicable to medically underappreciated populations. Therefore, their research provides a roadmap to use rich genomic information on PIEZO1 to explore how mechanotransduction contributes to human physiology and disease in unexpected ways. This study has been published in Cell in Feb 2021.

 

Sherry