IRON STORAGE PROTEIN TRAFFICKING AND ITS POSSIBLE ROLE IN NEURODEGENERATIVE DISEASES

INTRODUCTION: Ferritin in mammalians is mainly considered an intracellular cytosolic iron storage protein; however, possible functions of a secreted form in iron distribution in the brain have been demonstrated. Thus, we aimed to elucidate pathways of intracellular ferritin-trafficking between different subcellular compartments and possible routes for secretion.

METHODS: Subcellular fractionation and immunofluorescence were employed to analyse ferritin subcellular distribution in murine macrophages. The classical ER-Golgi secretion pathway and autophagy, as an example of an entry-point into non-classical pathways, were manipulated. Effects of these substances on intracellular ferritin distribution and its secretion were evaluated.

RESULTS and DISCUSSION: Subcellular fractionations and immunofluorescence demonstrated ferritin both in the cytosol and the lysosome, with significant enrichment of the lysosomally processed short L-subunit in the lysosomal fraction. This suggested both controlled processing and stability of ferritin in the lysosome. Ferritin secretion was not inhibited even when the Golgi was dissociated. Also, ferritin did not co-localize with the ER-Golgi machinery. Further, inhibition and activation of the autophagy pathway inhibited and activated ferritin secretion respectively. Moreover, we confirmed that ferritin co-localized with an autophagy receptor in these cells. Taking these results together we have evidence that cytosolic ferritin enters the endo-lysosomal machinery and utilizes two non-classical secretion routes involving lysosome-related organelles.

CONCLUSIONS: The aforementioned findings show that lysosomes play important roles in cellular trafficking and secretion of ferritin, shedding new light on possible functions for ferritin in tissue-iron distribution and cellular and systemic iron homeostasis. Specifically, ferritin secretion may play a central role in iron distribution in the brain and thus constitute an important link in the elucidation of the many neurodegenerative diseases accompanied by impaired iron-distribution in the brain.