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Iron Mobilization from Ferritin in Yeast Cell Lysate and Physiological Implications

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Smith, Gideon L., Srivastava, Ayush K., Reutovich, Aliaksandra A., Hunter, Nathan J., Arosio, Paolo, Melman, Artem, Bou-Abdallah, Fadi·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23116100PMC PMC9181690
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Abstract

Most in vitro iron mobilization studies from ferritin have been performed in aqueous buffered solutions using a variety of reducing substances. The kinetics of iron mobilization from ferritin in a medium that resembles the complex milieu of cells could dramatically differ from those in aqueous solutions, and to our knowledge, no such studies have been performed. Here, we have studied the kinetics of iron release from ferritin in fresh yeast cell lysates and examined the effect of cellular metabolites on this process. Our results show that iron release from ferritin in buffer is extremely slow compared to cell lysate under identical experimental conditions, suggesting that certain cellular metabolites present in yeast cell lysate facilitate the reductive release of ferric iron from the ferritin core. Using filtration membranes with different molecular weight cut-offs (3, 10, 30, 50, and 100 kDa), we demonstrate that a cellular component >50 kDa is implicated in the reductive release of iron. When the cell lysate was washed three times with buffer, or when NADPH was omitted from the solution, a dramatic decrease in iron mobilization rates was observed. The addition of physiological concentrations of free flavins, such as FMN, FAD, and riboflavin showed about a two-fold increase in the amount of released iron. Notably, all iron release kinetics occurred while the solution oxygen level was still high. Altogether, our results indicate that in addition to ferritin proteolysis, there exists an auxiliary iron reductive mechanism that involves long-range electron transfer reactions facilitated by the ferritin shell. The physiological implications of such iron reductive mechanisms are discussed.

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  • Mobilization of stored iron pools often requires reduction, or in some cases proteolysis, and occurs on a time-scale of minutes.

    “Mobilization of these stored iron pools often requires reduction,132 or in some cases proteolysis,127,133 and occurs on a time-scale of minutes.”

    From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [132]

    The Introduction (page unavailable) identifies lysosomal ferritin proteolysis as a primary mechanism for mobilizing iron from ferritin, and the Discussion also describes reductive mechanisms. The cited copy does not establish the claim’s minutes-long time scale; its Results discuss release kinetics extending over two hours. (LLM, conf=0.84)

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Authors
Smith, G. L., Srivastava, A. K., Reutovich, A. A., Hunter, N. J., Arosio, P., Melman, A., & Bou-Abdallah, F.
Affiliations
  • State University of New York at Potsdam (US)
  • University of Brescia (IT)
  • Clarkson University (US)
  • Department of Chemistry, State University of New York, Potsdam, NY 13676, USA
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-05-29
Volume
23
Issue
11
Pages
6100
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23116100
PMC
PMC9181690
OpenAlex
W4281737679
Cited by
10
References
6
Citations by year
2025: 2 · 2024: 2 · 2023: 3 · 2022: 3
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation, Division of Molecular and Cellular Biosciences (MCB) (1934666, #27452, R15GM104879)
  • Research Corporation for Science Advancement (1934666, #27452, R15GM104879)
  • National Institute of Health (1934666, #27452, R15GM104879)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
Keywords
ferritin, iron mobilization, iron release kinetics, cellular metabolites, NADPH, flavin, flavin mononucleotide, FAD, riboflavin, long-range electron transfer, Fe(III) reduction, molecular weight cut-off membranes
MeSH terms
Electron Transport, Ferritins, Iron, Kinetics, Riboflavin, Saccharomyces cerevisiae

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