An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
- University of Oxford, United Kingdom
Abstract
Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.
Article and author information
Author details
Samira Lakhal-Littleton
Funding
British Heart Foundation (FS/12/63/29895)
- Samira Lakhal-Littleton
Vifor Pharma (R19874-CN004)
- Magda Wolna
The funders funded the salary and research expenses relating to this work for two of the authors, as described above.
Ethics
Animal experimentation: All animal procedures were compliant with and approved under the UK Home Office Animals (Scientific Procedures) Act 1986 (Project Licence number 30/3182). In vivo assessment of cardiac function was carried out under anesthesia (2% Isofluorane) to minimize suffering.
Reviewing Editor
- Richard P Harvey, The Victor Chang Cardiac Research Institute, Australia
Publication history
- Received: July 19, 2016
- Accepted: November 24, 2016
- Accepted Manuscript published: November 29, 2016 (version 1)
- Version of Record published: December 21, 2016 (version 2)
Copyright
© 2016, Lakhal-Littleton et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
eLife 5:e19804.
https://doi.org/10.7554/eLife.19804
Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here, we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival.
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe2+) from cells and is important for homeostasis of iron in circulation. Export of one Fe2+ by Fpn is coupled to import of two H+ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca2+ transport. We determine the structure of Ca2+-bound HsFpn and identify a single Ca2+ binding site distinct from the Fe2+ binding sites. Further studies validate the Ca2+ binding site and show that Ca2+ transport is not coupled to transport of another ion. In addition, Ca2+ transport is significantly inhibited in the presence of Fe2+ but not vice versa. Function of Fpn as a Ca2+ uniporter may allow regulation of iron homeostasis by Ca2+.
