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J Struct Biol. 2014 Sep;187(3):254-265. doi: 10.1016/j.jsb.2014.07.002. Epub 2014 Jul 19.

Iron-rich ferritin in the hypoxia-tolerant rodent Spalax ehrenbergi: a naturally-occurring biomarker confirms the internalization and pathways of intracellular macromolecules.

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The Milman-David Biomedical Research Unit, 24 Hazevi Avenue, 34355 Haifa, Israel. Electronic address:
Weizmann Institute of Science, 234 Herzl St., Rehovot 76100, Israel. Electronic address:
Institute of Evolution, University of Haifa, Haifa 3498838, Israel. Electronic address:
Institute of Evolution, University of Haifa, Haifa 3498838, Israel. Electronic address:


The discovery of pits/caveolae in the plasmalemma advanced the study of macromolecule internalization. "Transcytosis" describes the transport of macromolecular cargo from one front of a polarized cell to the other within membrane-bounded carrier(s), via endocytosis, intracellular trafficking and exocytosis. Clathrin-mediated transcytosis is used extensively by epithelial cells, while caveolae-mediated transcytosis mostly occurs in endothelial cells. The internalization pathways were monitored by various markers, including radioisotopes, nanoparticles, enzymes, immunostains, and fluorophores. We describe an internalization pathway identified using a naturally-occurring biomarker, in vivo assembled ferritin, containing electron-dense iron cores. Iron, an essential trace metal for most living species and iron homeostasis, is crucial for cellular life. Ferritin is a ubiquitous and highly conserved archeoprotein whose main function is to store a reserve iron supply inside the cytoplasm in a non-toxic form. Ferritin is present in all organisms which have a metabolic requirement for iron and in even in organisms whose taxonomic rank is very low. The newborns of the blind mole, Spalax ehrenbergi, are born and live in a hypoxic environment and have significant iron overload in their liver and heart, but their iron metabolism has not been previously studied. These newborns, which are evolutionarily adapted to fluctuations in the environmental oxygen, have a unique ability to sequester transplacental iron and store it in ferritin without any signs of iron toxicity. Using the ferrihydrite cores of ferritin, we were able to monitor the ferritin internalization from portals of its entry into the cytosol of hepatocytes and cardiomyocytes and into the lysosomes.


Caveolae; Endocytosis; Ferritin; Internalization; Iron; Spalax ehrenbergi

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