3D morphology of the human hepatic ferritin mineral core: new evidence for a subunit structure revealed by single particle analysis of HAADF-STEM images.

Ferritin, the major iron storage protein, has dual functions; it sequesters redox activity of intracellular iron and facilitates iron turn-over. Here we present high angle annular dark field (HAADF) images from individual hepatic ferritin cores within tissue sections, these images were obtained using spherical aberration corrected scanning transmission electron microscopy (STEM) under controlled electron fluence. HAADF images of the cores suggest a cubic morphology and a polycrystalline (ferrihydrite) subunit structure that is not evident in equivalent bright field images. By calibrating contrast levels in the HAADF images using quantitative electron energy loss spectroscopy, we have estimated the absolute iron content in any one core, and produced a three dimensional reconstruction of the average core morphology. The core is composed of up to eight subunits, consistent with the eight channels in the protein shell that deliver iron to the central cavity. We find no evidence of a crystallographic orientation relationship between core subunits. Our results confirm that the ferritin protein shell acts as a template for core morphology and within the core, small (approximately 2 nm), surface-disordered ferrihydrite subunits connect to leave a low density centre and a high surface area that would allow rapid turn-over of iron in biological systems.

Ultrastructural pathology of the heart in patients with beta-thalassaemia major.

Patients with beta-thalassaemia major frequently suffer from hypersiderosis which leads to hemochromatosis of major organs such as the heart and liver. Little information exists about the ultrastructural pathology of the human heart in beta-thalassaemia patients. Five Cypriot patients with elevated blood ferritin and intractable heart failure were investigated. Cardiac biopsies from these patients were studied by light and electron microscopy, as well as by X-ray microanalysis. Ultrastructural examination revealed the presence of disrupted myocytes showing loss of myofibers, dense nuclei, and a variable number of pleomorphic electron dense granules. These cytoplasmic granules or siderosomes consisted of iron-containing particles as confirmed by X-ray microanalysis. It is likely that the ultrastructural changes observed in myocytes of patients with beta-thalassaemia are largely due to iron deposition.

Spindle cell endocrine carcinoma of the mammary gland.

We report the pathological characteristics of a variant of mammary endocrine tumour, predominantly formed from cytologically bland spindle cells. This neoplasm grows as a red, well defined mass lacking the usual macroscopical characteristics of breast cancer. Within smoothly contoured aggregates arranged in an insular pattern, delicate capillaries and collagen bundles support the neoplastic epithelial cells. Most of the tumour cells possess a slender spindle shape and form a solid or fenestrated sheet, but a few appear cuboidal and create glands. Immunohistochemical studies demonstrate that the spindle cells and the glandular cells constitute a single population. Both types of cells stain for neuroendocrine markers (chromogranin, synaptophysin, and CD 57), carcinoembryonic antigen, keratin 8/18, S-100 protein, and receptors for oestrogen and progesterone. Many of the tumour cells possess argyrophilic granules, and electron microscopy may reveal dense core granules.

Studies on haemosiderin and ferritin from iron-loaded rat liver.

Haemosiderin has been isolated from siderosomes and ferritin from the cytosol of livers of rats iron-loaded by intraperitoneal injections of iron-dextran. Siderosomal haermosiderin, like ferritin, was shown by electron diffraction to contain iron mainly in the form of small particles of ferrihydrite (5Fe2O3.9H2O), with average particle diameter of 5.36 +/- 1.31 nm (SD), less than that of ferritin iron-cores (6.14 +/- 1.18 nm). Mössbauer spectra of both iron-storage complexes are also similar, except that the blocking temperature, TB, for haemosiderin (23 K) is lower than that of ferritin (35 K). These values are consistent with their differences in particle volumes assuming identical magnetic anisotropy constants. Measurements of P/Fe ratios by electron probe microanalysis showed the presence of phosphorus in rat liver haemosiderin, but much of it was lost on extensive dialysis. The presence of peptides reacting with anti-ferritin antisera and the similarities in the structures of their iron components are consistent with the view that rat liver haemosiderin arises by degradation of ferritin polypeptides, but its peptide pattern is different from that found in human beta-thalassaemia haemosiderin. The blocking temperature, 35 K, for rat liver ferritin is near to that reported, 40 K, for human beta-thalassaemia spleen ferritin. However, the haemosiderin isolated from this tissue, in contrast to that from rat liver, had a TB higher than that of ferritin. The iron availability of haemosiderins from rat liver and human beta-thalassaemic spleen to a hydroxypyridinone chelator also differed. That from rat liver was equal to or greater, and that from human spleen was markedly less, than the iron availability from either of the associated ferritins, which were equivalent. The differences in properties of the two types of haemosiderin may reflect their origins from primary or secondary iron overload and differences in the duration of the overload.