Alterations in tissue ferritins in iron storage disorders.

Abstract

SUMMARY Purified tissue ferritins isolated from Bantu subjects with gross haemosiderosis, from a patient with idiopathic haemochromatosis ( HC) treated by phlebotomy, and from rats with experimental iron overload were studied in order to determine the significance of the abnormality previously demonstrated in tissue isoferritins in patients with IHC. The isoferritin profile of the tissues from the Bantu subjects and the iron-loaded rats showed a similar abnormality to that previously found in patients with untreated IHC-that is, an abnormally uniform distribution of iron-containing isoferritins with an increase in the more basic isoferritins and an apparent absence of the more acidic ones. In contrast, tissues from the patient with treated IHC, who was iron depleted at the time of death, showed the normal organ-specific isoferritin distribution. These findings strongly suggest that the abnormal distribution of tissue isoferritins in IHC is an acquired phenomenon and unlikely to be related to an underlying genetic defect in ferritin or iron metabolism.Ferritin is the major iron storage protein in mammalian tissues and is found, or may be induced by iron administration, in most organs (Granick, 1951;Munro and Drysdale, 1970). Many tissue ferritins have been resolved into multiple isoferritins by the technique of isoelectric focusing Urushizaki et al., 1971;Drysdale, 1974;Powell et al., 1975). These isoferritins do not represent differences in aggregation or iron content of the protein but intrinsically different apoferritin shells 1974). Each tissue appears to have a characteristic isoferritin composition (Drysdale, 1974;Powell et al., 1975). This organ-specific isoferritin profile has recently been shown to be markedly abnormal in patients with untreated primary idiopathic haemochromatosis . The present study was designed to determine whether the abnormality in tissue isoferritins in idiopathic haemochromatosis is directly related to the genetic defect in iron metabolism or the result of long-standing iron overload. Methods HUMAN TISSUESNecropsy tissues were obtained from a normal adult male accident victim and also from a patient with classical familial idiopathic haemochromatosis whose case history and family history have been documented previously (Powell, 1965). This patient Received for publication 18 September 1975. had been treated by repeated phlebotomy for 11 years and was in a state of marginal iron deficiency at the time of his death at the age of 74 years. Histological examination showed no stainable iron in any of the tissues examined. Tissues from two Bantu patients with gross haemosiderosis were kindly provided by Professor R. Charlton of Johannesburg. ANIMAL STUDIESTen male Sprague Dawley rats weighing 250 to 300 g were each given 1 g/kg body weight of iron as irondextran by intramuscular injection over a period of two weeks. The rats were maintained on a normal diet tor three months and then killed by exsanguination from the dorsal aorta under ether anaesthesia. The carcasses were then perfuse...

Variation in the distribution of two human heart ferritin species. Isoferritin profile and subunit composition in normal and iron-overloaded subjects

“…Acidic ferritins were demonstrated by isoelectric focusing in the four preparations from iron-loaded subjects, and these were the most prominent isoferritins in three of the four preparations. These findings do not agree with those of Powell et al (1974Powell et al ( , 1975b, who reported that with long-standing iron overload there was a loss of acidic isoferritins from heart. In our study there was no consistent pattern of isoferritin distribution, even in iron overload, and it is thus possible that the effects of iron overload are superimposed on the same type of variable isoferritin pattern as seen in the normal subjects.…”

Heterogeneity in horse ferritins. A comparative study of surface charge, iron content and kinetics of iron uptake

“…We first thought that, if the Drysdale (1977) hybrid scheme were correct, then some functional correlation might be expected between surface charge (a putative indicator ofthe proportions of H and L subunits) and ability to sequester iron. It has been reported that in rats and humans iron overload leads to a replacement of heart-type by liver-type ferritins in heart tissue itself (Powell et al, 1975b(Powell et al, , 1977, which might suggest a difference in ability of different ferritins to sequester iron. However, Bomford et al (1977) observed no consistent correlation between iron-loading and the proportion of L-type ferritin.…”

A career forged in iron

“…The work showed that tissue ferritins are hybrid molecules consisting of different proportions of different subunits, with the heavy H subunit predominating in heart and the light L subunit predominating in liver. In HC, the ratio of the different isoferritins changed with the H subunit predominating, although we later showed that this was the result of tissue iron loading and it was not specific for HC . Serum ferritin differs with an extra subunit and very little iron.…”

“…In HC, the ratio of the different isoferritins changed with the H subunit predominating, 10 although we later showed that this was the result of tissue iron loading and it was not specific for HC. [11][12][13] Serum ferritin differs with an extra subunit and very little iron. Its function is still unclear and the subject of current research by my colleague, Grant Ramm, at the Queensland Institute of Medical Research (QIMR; now QIMR Berghofer [vide infra]).…”