Abstract
In mammals, hundreds of proteins use iron in a multitude of cellular functions, including vital processes such as mitochondrial respiration, gene regulation and DNA synthesis or repair. Highly orchestrated regulatory systems control cellular and systemic iron fluxes ensuring sufficient iron delivery to target proteins is maintained, while limiting its potentially deleterious effects in iron-mediated oxidative cell damage and ferroptosis. In this Review, we discuss how cells acquire, traffick and export iron and how stored iron is mobilized for iron–sulfur cluster and haem biogenesis. Furthermore, we describe how these cellular processes are fine-tuned by the combination of various sensory and regulatory systems, such as the iron-regulatory protein (IRP)–iron-responsive element (IRE) network, the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy pathway, the prolyl hydroxylase domain (PHD)–hypoxia-inducible factor (HIF) axis or the nuclear factor erythroid 2-related factor 2 (NRF2) regulatory hub. We further describe how these pathways interact with systemic iron homeostasis control through the hepcidin–ferroportin axis to ensure appropriate iron fluxes. This knowledge is key for the identification of novel therapeutic opportunities to prevent diseases of cellular and/or systemic iron mismanagement.
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Change history
26 June 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41580-024-00760-w
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Acknowledgements
The authors thank S. Altamura (University of Heidelberg) for help with retrieving data on iron proteins and N. Gunkel (German Cancer Research Center (DKFZ)) for critical feedback on the manuscript. B.G. is the recipient of a grant from the Deutsche Forschungsgemeinschaft (DFG) (GA 2075/6-1). M.U.M. acknowledges funding from the DFG (FerrOs FOR5146, Priority Program SPP 2306, GRK2727), Federal Ministry of Education and Research (BMBF) (NephrESA project Nr 031L0191C), Dietmar Hopp-Stiftung and Deutscher Akademischer Austauschdienst (A New Passage to India). M.C. acknowledges funding from the DFG (CO 291/9-1, #461385412; and the Priority Program SPP 2306 (CO 291/9-1, #461385412; CO 291/10-1, #461507177)), BMBF (FERROPath 01EJ2205B), Else Kröner-Fresenius-Stiftung (Projects 2019_T12, 2020_EKTP19) and European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. GA 884754). The original figures were generated with the assistance of BioRender.
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Glossary
- Capsular cells
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Stromal cells in the outermost layer of the renal cortex that provide a signalling environment crucial for normal patterning of the developing kidney.
- Exocyst octameric complex
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A multi-subunit protein complex (composed of eight subunits) that is recruited to sites of active exocytosis where it facilitates the tethering of secretory vesicles to the plasma membrane prior to fusion.
- Fenton chemistry
-
The catalytic decomposition of hydrogen peroxide (H2O2) into a hydroxide ion (OH−) and a hydroxyl radical (HO•) by ferrous iron; named after the British chemist H. J. H. Fenton (1854–1929).
- Hepatic stellate cells
-
(HSCs). Liver cells located between liver sinusoidal endothelial cells (LSECs) and hepatocytes that store vitamin A when quiescent. In response to liver damage, HSCs become activated and produce extracellular matrix proteins that promote liver fibrogenesis.
- Intermediary metabolism
-
The sum of anabolic and catabolic reactions that provide cells with metabolic energy, reducing power and biosynthetic intermediates.
- Kupffer cells
-
Hepatic macrophages residing in the liver sinusoids, whose function includes breaking down red blood cells (RBCs) by phagocytosis in order to recycle the iron contained in haemoglobin.
- L-type and T-type calcium channels
-
(Long-lasting-type and transient-type calcium channels). Voltage-dependent channels that allow calcium ions to flow into excitable cells, resulting in muscle contraction, neuron excitation, neurotransmitter release or gene regulation.
- Membrane–organelle-based secretion
-
An unconventional mode of protein secretion in which cargo proteins lacking signal peptides are incorporated into membrane intermediates derived from lysosomes, endosomes or the autophagy machinery and released into the extracellular space after exocytosis.
- Reticuloendothelial system
-
A heterogeneous population of phagocytic cells (mainly monocytes and macrophages) whose function includes the removal of foreign particles or old or damaged cells from the circulation.
- Toll-like receptors
-
(TLRs). Single-pass membrane receptors that recognize molecules from infectious agents or endogenous damage signals and activate a signalling cascade stimulating immune cell responses.
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Cite this article
Galy, B., Conrad, M. & Muckenthaler, M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol 25, 133–155 (2024). https://doi.org/10.1038/s41580-023-00648-1
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DOI: https://doi.org/10.1038/s41580-023-00648-1
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