ON THE CYTOPROTECTIVE ROLE OF FERRITIN IN MACROPHAGES AND ITS ABILITYTO ENHANCE LYSOSOMAL STABILITY

Macrophages have a great capacity to take up (e.g. by endocytosis and phagocytosis) exogenous sources of iron which could potentially become cytotoxic, particularly following the intralysosomal formation of low -molecular weight, redox active iron, and under conditions of oxidativ e stress. Following autophagocytosis of endogenous ferritin/apoferriti n, these compounds may serve as chelators of such lysosomal iron and c ounteract the occurrence of iron-mediated intralysosomal oxidative rea ctions. Such redox-reactions have been shown to lead to destabilisatio n of lysosomal membranes and result in leakage of damaging lysosomal c ontents to the cytosol. In this study we have shown: (i) human monocyt e-derived macrophages to accumulate ferritin in response to iron expos ure; (ii) iron to destabilise macrophage secondary lysosomes when the cells are exposed to H2O2; and (iii) endocytosed apoferritin to act as a stabiliser of the acidic vacuolar compartment of iron-loaded macrop hages. While the endogenous ferritin accumulation which was induced by iron exposure was not sufficient to protect cells from the damaging e ffects of H2O2, exogenously added apoferritin, as well as the potent i ron chelator desferrioxamine, afforded significant protection. It is s uggested that intralysosomal formation of haemosiderin, from partially degraded ferritin, is a protective strategy to suppress intralysosoma l iron-catalysed redox reactions. However, under conditions of severe macrophage lysosomal iron-overload, induction of ferritin synthesis is not enough to completely prevent the enhanced cytotoxic effects of H2 O2.