Human mitochondrial ferritin exhibits highly unusual iron-O2 chemistry distinct from that of cytosolic ferritins

Bradley, Justin M., Bugg, Zinnia, Pullin, Jacob, Moore, Geoffrey R., Svistunenko, Dimitri A. and Le Brun, Nick E. (2025) Human mitochondrial ferritin exhibits highly unusual iron-O2 chemistry distinct from that of cytosolic ferritins. Nature Communications, 16. ISSN 2041-1723

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Abstract

Ferritins are ubiquitous proteins that function in iron storage/detoxification by catalyzing the oxidation of Fe2+ ions and solubilizing the resulting Fe3+-oxo mineral. Mammalian tissues that are metabolically highly active contain, in addition to the widespread cytosolic ferritin, a ferritin that is localized to mitochondria. Mitochondrial ferritin (FtMt) protects against oxidative stress and is found at higher levels in diseases associated with abnormal iron accumulation, including Alzheimer’s and Parkinson’s. Here we demonstrate that, despite 80% sequence identity with cytosolic human H-chain ferritin, Fe2+ oxidation at the catalytic diiron ferroxidase center of FtMt proceeds via a distinct mechanism. This involves a mixed-valent ferroxidase center (MVFC) that is readily detected under the O2-limiting conditions typical of mitochondria, and formation of a radical on a strictly conserved Tyr residue (Tyr34) that is key for the activation of O2 and stability of the MVFC. The possible origin of the mechanistic differences exhibited by the highly-related human mitochondrial and cytosolic H-chain ferritins is explored.

Item Type:	Article
Additional Information:	Data availability: All data supporting the findings of this study are available within the paper and its Supplementary Information. Source data are provided with this paper. Expression constructs are available upon request from Nick Le Brun (n.le-brun@uea.ac.uk). Source data are provided with this paper. Acknowledgements: The authors wish to thank Dr Andrew Gates (UEA) for access to the stopped-flow instrument. This work was supported by the UK’s Biotechnology and Biological Sciences Research Council through grants BB/R002363/1 (J.M.B. and N.L.B.), BB/R003203/1 (D.A.S.) and BB/T01802X/1 (D.A.S.) and by UEA.
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science
UEA Research Groups:	Faculty of Science > Research Groups > Chemistry of Life Processes Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	28 Apr 2025 15:30
Last Modified:	27 Jun 2025 08:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99128
DOI:	10.1038/s41467-025-59463-1

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