title: Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit.
abstract: Cytosolic ferritins sequester and store iron, consequently protecting cells against iron-mediated free radical damage. However, the mechanisms of iron exit from the ferritin cage and reutilization are largely unknown. In a previous study, we found that mitochondrial ferritin (MtFt) expression led to a decrease in cytosolic ferritin. Here we showed that treatment with inhibitors of lysosomal proteases largely blocked cytosolic ferritin loss in both MtFt-expressing and wild-type cells. Moreover, cytosolic ferritin in cells treated with inhibitors of lysosomal proteases was found to store more iron than did cytosolic ferritins in untreated cells. The prevention of cytosolic ferritin degradation in MtFt-expressing cells significantly blocked iron mobilization from the protein cage induced by MtFt expression. These studies also showed that blockage of cytosolic ferritin loss by leupeptin resulted in decreased cytosolic ferritin synthesis and prolonged cytosolic ferritin stability, potentially resulting in diminished iron availability. Lastly, we found that proteasomes were responsible for cytosolic ferritin degradation in cells pretreated with ferric ammonium citrate. Thus, the current studies suggest that cytosolic ferritin degradation precedes the release of iron in MtFt-expressing cells; that MtFt-induced cytosolic ferritin decrease is partially preventable by lysosomal protease inhibitors; and that both lysosomal and proteasomal pathways may be involved in cytosolic ferritin degradation.
authors.affiliation: CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Marc
authors.initials: M
authors.lastname: Mikhael
authors.forename: Dongxue
authors.initials: D
authors.lastname: Xu
authors.forename: Yiye
authors.initials: Y
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Soe-Lin
authors.forename: Bo
authors.initials: B
authors.lastname: Ning
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Prem
authors.initials: P
authors.lastname: Ponka
mesh_terms: D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D005290:Ferric Compounds / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology
chemical_list: D005290:Ferric Compounds; D007976:Leupeptins; D011480:Protease Inhibitors; D000644:Quaternary Ammonium Compounds; D005293:Ferritins; D007501:Iron; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C032854:leupeptin; C013531:ferric ammonium citrate