|Ph.D Student||Cohen Lyora|
|Subject||Characterization of Mouse Serum Ferritin and Mechanism|
of Ferritin Secretion
|Department||Department of Biotechnology and Food Engineering||Supervisor||Professor Esther Meyron Holtz|
|Full Thesis text|
Ferritin is an iron storage protein that is found in prokaryotes, plants and higher eukaryotes. Two subunits, H- and L-, form a 24-mer cage that stores up to 4500 iron atoms in its core. In mammals, ferritin is mostly cytosolic and its expression is regulated posttranscriptionally by the iron regulatory proteins (IRP) 1 and 2. A secreted form of ferritin is found in serum and levels of serum ferritin usually correlate well with levels of body iron stores. Exceptions to this correlation are pathologic states such as chronic inflammation and several kinds of cancer where serum ferritin levels are elevated. The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of ferritin secretion, we have used traditional and modern methodologies in order to characterize mouse serum ferritin as a model of secreted ferritin.
Our results suggest that serum ferritin is composed mostly of L-subunits, contains few H-subunits and iron content is low. The amino-acid composition of the two subunits is identical with intracellular ferritin, suggesting that they origin from the same gene. All serum ferritin is assembled to 24-mer-nanocages and the unique subunit ratio suggests that it consists mainly of L-subunit homo-polymers and only some hetero-polymers. In addition serum ferritin is not N-glycosylated, which let us hypothesize that ferritin may not be secreted through the classical secretion pathway.
We also find that both, macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells.
L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17 kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that serum ferritin represents a subpopulation of intracellular ferritin that has translocated to the lysosomal compartment. From the lysosome, ferritin can be secreted through the secretory-lysosomal pathway.
This ferritin secretion pathway may represent an important and underappreciated mechanism by which cells can regulate and secrete iron.