Iron as spirit of life to share under monopoly

Our plain-English summary of Iron as spirit of life to share under monopoly, by S. Toyokuni, Y. Kong, H. Zheng, et al (Journal of Clinical Biochemistry and Nutrition, 2022).

The study

• Authors: S. Toyokuni, Y. Kong, H. Zheng, Y. Maeda, Y. Motooka, S. Akatsuka
• Journal: Journal of Clinical Biochemistry and Nutrition
• Published: 2022;71(2):78-88
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

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In plain English

This article was a review, not a new study. The authors, from a pathology laboratory at Nagoya University in Japan, described the history and recent findings of their own research on iron, along with work by others. Much of it covered a rat and mouse model in which repeated injections of an iron compound, ferric nitrilotriacetate (Fe-NTA), caused kidney cancer. The authors described earlier findings that these cancers commonly showed deletion of the p16Ink4a gene and amplification of the c-Met gene. On asbestos, the review described the laboratory's earlier findings in this sequence. Macrophages beneath the mesothelium collect asbestos fibers but cannot digest them, and they die by an iron-dependent process called ferroptosis. As they die, they release small vesicles carrying iron-loaded ferritin. Mesothelial cells take up these vesicles, eventually causing oxidative DNA damage. The review also stated that mesothelioma cells hold more catalytic iron, Fe(II), than non-tumorous cells. The authors concluded that their findings support the idea of excess iron as a risk for cancer. They noted that the work on iron-loaded vesicles from human fibroblasts was done only in cultured cells, and that receptors for these vesicles have not been conclusively identified.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of the authors' laboratory research and related literature
• Who was studied: no new study population; the review covered the laboratory's research since the 1980s, mainly rodent models, cultured human cells and rats, plus cited literature
• Exposure: mainly ferric nitrilotriacetate (Fe-NTA) injections in rodents; for asbestos, fibers (type not specified in the text) collected by macrophages beneath the mesothelium
• Main results:
  • In kidney cancers induced by Fe-NTA in rodents (earlier lab work), deletion of p16Ink4a and amplification of c-Met were the common mutations
  • In human fibroblast cells (IMR90), iron loading increased CD63 protein through the IRE/IRP system, and more vesicles containing iron-loaded ferritin were released (earlier lab work)
  • Macrophages that take up asbestos fibers cannot digest them and undergo ferroptosis with large amounts of iron inside (earlier lab work)
  • Vesicles released by these macrophages (FedEVs) contain iron-loaded ferritin and are taken up by mesothelial cells, eventually causing oxidative DNA damage (earlier lab work)
  • Mesothelioma cells were described as holding more catalytic Fe(II) than non-tumorous cells
  • A preclinical treatment, plasma-activated lactate Ringer's solution (PAL), caused ferroptosis specifically in mesothelioma cells compared with mesothelial cells
  • In rats, ferroptotic cells increased with aging in several organs
• The authors' conclusion: The authors concluded that their findings support the idea of excess iron as a risk for cancer.
• Limitations the authors state:
  • The CD63 and ferritin-secretion finding came from cell culture only; further study is needed on ferritin secretion into the serum
  • Receptors for vesicles containing iron-loaded ferritin have not been unequivocally identified yet
  • The antibody used to detect ferroptosis (HNEJ-1) comes from mice, so results in mouse models need careful interpretation
  • The figure on physiological ferroptosis is partly hypothetical

Topics

Medical terms in this study, explained in our Lexicon: Necrosis, Carcinogenesis, Ferritin.

Related studies

• Formation of asbestos bodies under the influence of parenteral iron overload — S. Narang, J.L. Kaw, et al. (1978)
• Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles — S. Toyokuni, Y. Kong, et al. (2021)
• Cell proliferation and carcinogenesis may share a common basis of permeable plasma membrane clusters — J.A. Beech (1992)
• Iron overload signature in chrysotile-induced malignant mesothelioma — L. Jiang, S. Akatsuka, et al. (2012)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)

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