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Iron Stories

Iron and Oxygen Homeostasis — Parallels as well as Intersections

Samira Lakhal-Littleton, PhD

It is undisputed that there are many intersections between iron and oxygen at the cellular and systems levels. At the cellular level, iron is required for the utilisation of oxygen in oxidative phosphorylation, for the storage of oxygen in myoglobin, and for the sensing of oxygen by Hypoxia-inducible Factor (HIF) prolyl hydroxylases (PHDs). At the systems level, iron is required for the transport of oxygen around our bodies, and for the finetuning of physiological responses to hypoxia, such as erythropoiesis and pulmonary vasoconstriction.

Over the past few years, I have come to realise there are parallels as well as intersections. I can see the parallels clearly now, having had the benefit, and privilege, of starting out as a young researcher in oxygen homeostasis under the tutelage of Sir Peter Ratcliffe, then moving on to pursue an independent career in iron homeostasis.

Two lines of symmetry have started to crystallise in my mind. The first line of symmetry is the way in which a homeostatic pathway initially discovered in a specific system turns out to be universally important. This is true of HIFs, initially discovered as regulators of erythropoietin in the kidney, only for later discoveries to show that virtually every cell uses them to sense and to respond to changes in oxygen availability1. This is paralleled in the hepcidin/ferroportin axis. It was first described as the orchestrator of systemic iron homeostasis, but there is now a growing body of evidence that hepcidin/ferroportin axes operate locally in many tissues to control local iron homeostasis2-8. This parallelism is apparent when scouring recent iron literature and is further reinforced when you consider the way in which both the HIF system and the local hepcidin/ferroportin axis are appropriated by cancer cells to their advantage3,9. Of course, it remains to be seen if the hepcidin/ferroportin axis is as universally used for iron homeostasis as the HIF system is for oxygen homeostasis.

The second line of symmetry is the way in which both the HIF system and the hepcidin/ferroportin axis have built-in “prophylactic” safeguards against the otherwise catastrophic consequences of, respectively, a rapid drop in oxygen availability, and a rapid rise in in the intracellular iron pool. HIF proteins are continuously synthesised and degraded in the oxygen-sufficient cell, a set-up that is necessary to ensure HIF proteins are available for instant stabilisation should oxygen levels in the cell drop. This safeguard allows cells to quickly trigger the transcriptional reprogramming necessary for coping with low oxygen levels10. The expression of ferroportin in many tissues is9, 11-14, in my view, also a safeguard, a type of sophisticated overflow system in the face of potentially harmful fluctuations in the intercellular iron pool. For instance, removal of ferroportin from the cardiac myocytes leads to fatal iron overload cardiomyopathy and is not compensated for by a reduction in the expression of iron-uptake proteins14. It remains to be seen if this iron “overflow system” operates universally in all tissues, and whether its physiological importance in a given tissue relates to local iron flux.

There is yet a lot to be probed and discovered within both fields of research. Nonetheless, it is tantalising to think the journey of the hepcidin/ferroportin axis could take a similar trajectory to that of HIF system, i.e., towards defining the fundamentals of homeostatic control, and ultimately towards smarter ways to restore such control when it goes astray.

References
  1. Pan SY, Chiang WC, Chen YM. The journey from erythropoietin to 2019 Nobel Prize: Focus on hypoxia-inducible factors in the kidney. J Formos Med Assoc. 2021 Jan;120(1 Pt 1):60-67.
  2. Chaudhary S, Ashok A, McDonald D, Wise AS, Kritikos AE, Rana NA, Harding CV, Singh N. Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer's Disease Brains. J Alzheimers Dis. 2021 Jun 19. doi: 10.3233/JAD-210221.
  3. Schwartz AJ, Goyert JW, Solanki S, Kerk SA, Chen B, Castillo C, Hsu PP, Do BT, Singhal R, Dame MK, Lee HJ, Spence JR, Lakhal-Littleton S, Heiden MGV, Lyssiotis CA, Xue X, Shah YM. Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells. Nat Metab. 2021 Jul;3(7):969-982.
  4. Kämmerer, L.; Mohammad, G.; Wolna, M.; Robbins, P.A.; Lakhal-Littleton, S. Fetal liver hepcidin secures iron stores in utero. Blood 2020, 136, 1549–1557.
  5. Bessman, N.J.; Mathieu, J.R.R.; Renassia, C.; Zhou, L.; Fung, T.C.; Fernandez, K.C.; Austin, C.; Moeller, J.B.; Zumerle, S.; Louis, S.; et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 2020, 368, 186–189.
  6. Perez E, Baker JR, Di Giandomenico S, Kermani P, Parker J, Kim K, Yang J, Barnes PJ, Vaulont S, Scandura JM, Donnelly LE, Stout-Delgado H, Cloonan SM. Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model. J Immunol. 2020 Nov 1;205(9):2489-2498.
  7. Lakhal-Littleton S, Crosby A, Frise MC, Mohammad G, Carr CA, Loick PAM and Robbins PA. Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice. Proc Natl Acad Sci U S A. 2019;116:13122-13130.
  8. Lakhal-Littleton S, Wolna M, Chung YJ, Christian HC, Heather LC, Brescia M, Ball V, Diaz R, Santos A, Biggs D, Clarke K, Davies B and Robbins PA. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. Elife. 2016;5.
  9. Rashid M, Zadeh LR, Baradaran B, Molavi O, Ghesmati Z, Sabzichi M, Ramezani F. Up-down regulation of HIF-1α in cancer progression. Gene. 2021 Sep 25;798:145796.
  10. Recalcati, S.; Gammella, E.; Buratti, P.; Doni, A.; Anselmo, A.; Locati, M.; Cairo, G. Macrophage ferroportin is essential for stromal cell proliferation in wound healing. Haematologica 2019, 104, 47–58.
  11. Schofield CJ, Ratcliffe PJ. Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun. 2005 Dec 9;338(1):617-26.
  12. Yang, F.; Haile, D.J.; Wang, X.; Dailey, L.A.; Stonehuerner, J.G.; Ghio, A.J. Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 2005, 289, L14–L23. 
  13. Leichtmann-Bardoogo Y, Cohen LA, Weiss A, Marohn B, Schubert S, Meinhardt A, Meyron-Holtz EG. Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload. Am J Physiol Endocrinol Metab. 2012 Jun 15;302(12):E1519-30.
  14. Lakhal-Littleton S, Wolna M, Carr CA, Miller JJ, Christian HC, Ball V, Santos A, Diaz R, Biggs D, Stillion R, Holdship P, Larner F, Tyler DJ, Clarke K, Davies B and Robbins PA. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. Proc Natl Acad Sci U S A. 2015;112:3164-9.

posted: August 9, 2021