A role of PIEZO1 in iron metabolism in mice and humans
Open accessAbstract
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.
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BMDMs from Piezo1fl/fl Lyz2Cre mice were usually smaller than BMDMs from Piezo1fl/fl mice.
“In addition, we found that BMDMs from Piezo1fl/fl Lyz2Cre mice were usually smaller than BMDMs from Piezo1fl/fl mice (Fig. 5C), attributed to the deficiency of Piezo1 impairing the calcium influx and downstream cytoskeletal organization in BMDMs (16, 23).”
From Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis (2024) · cites this paper as [16]
The Results sections report that PIEZO1 conducts calcium, that Rac1 regulates cytoskeletal organization, and that loss-of-function BMDMs have reduced Rac1 activity during phagocytosis (page unavailable). These findings support elements of the cited mechanistic explanation, but the paper does not report that the deficient BMDMs are smaller or establish that impaired calcium influx and cytoskeletal organization cause that size difference. (LLM, conf=0.85)
Experimental — accuracy not yet measuredConstitutive or macrophage-specific expression of a GOF Piezo1 allele in mice disrupts the expression of the iron regulator hepcidin, leading to iron overload.
“Recent studies demonstrate that constitutive or macrophage-specific expression of a GOF Piezo1 allele in mice disrupts the expression of the iron regulator hepcidin, leading to iron overload.”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [74]
Piezo1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover.
“Furthermore, these studies show that Piezo1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover.74”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [74]
Aged mice with specific Piezo1 GOF mutations exhibit progressive hepatic iron accumulation compared to wild-type controls, with elevated serum transferrin saturation and ferritin and increased hepatic macrophage iron staining.
“Ma et al., who reported that aged mice with specific Piezo1 GOF mutations exhibited progressive hepatic iron accumulation compared to wild-type controls. Serum transferrin saturation and ferritin levels were elevated, and increased hepatic macrophage iron staining was observed.”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [74]
In homozygous Piezo1 mutant mice, iron deposition is more pronounced than in heterozygotes, indicating age-dependent hepatic iron overload.
“In homozygous Piezo1 mutant mice, iron deposition is more pronounced than in heterozygotes, indicating age-dependent hepatic iron overload.74”
From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [74]
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References 75 · Cited by 232
Research works printed but not linked: 1
- Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood 126, 2031– 2037. PMC4616236 26276665
- Authors
- Ma, S., Dubin, A. E., Zhang, Y., Mousavi, S. A. R., Wang, Y., Coombs, A. M., Loud, M., Andolfo, I., & Patapoutian, A.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Naples Federico II (IT)
- Corresponding author
- Patapoutian, Ardem
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 184
- Issue
- 4
- Pages
- 969-982.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7927959
- OpenAlex
- W3126353694
- Cited by
- 232
- References
- 75
- Citations by year
- 2026: 37 · 2025: 46 · 2024: 53 · 2023: 46 · 2022: 32 · 2021: 18
- FWCI
- 24.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Keywords
- Piezo1, iron overload, iron homeostasis, hereditary xerocytosis, gain-of-function mutations, hepcidin, erythrocyte turnover, phagocytosis, African Americans, genetic risk factors, plasma iron
- MeSH terms
- Gain of Function Mutation, Aging, Alleles, Animals, Black or African American, Erythrocyte Count, Erythropoiesis, Humans, Ion Channels, Iron, Macrophages, Mice, Inbred C57BL, Phagocytosis, Phenotype, Stress, Physiological, Cohort Studies, Iron Overload, Hepatocytes, Mechanotransduction, Cellular, Mice, Hepcidins
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