Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit

Yinghui Zhang, Marc Mikhael, Dongxue Xu, Yiye Li, Shan Soe-Lin, Bo Ning, Wei Li, Guangjun Nie, Yuliang Zhao, Prem Ponka

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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.

Original languageEnglish (US)
Pages (from-to)999-1009
Number of pages11
JournalAntioxidants and Redox Signaling
Volume13
Issue number7
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

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Proteolysis
Ferritins
Iron
Degradation
Protease Inhibitors
Peptide Hydrolases

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. / Zhang, Yinghui; Mikhael, Marc; Xu, Dongxue; Li, Yiye; Soe-Lin, Shan; Ning, Bo; Li, Wei; Nie, Guangjun; Zhao, Yuliang; Ponka, Prem.

In: Antioxidants and Redox Signaling, Vol. 13, No. 7, 01.10.2010, p. 999-1009.

Research output: Contribution to journalArticle

Zhang, Yinghui ; Mikhael, Marc ; Xu, Dongxue ; Li, Yiye ; Soe-Lin, Shan ; Ning, Bo ; Li, Wei ; Nie, Guangjun ; Zhao, Yuliang ; Ponka, Prem. / Lysosomal proteolysis is the primary degradation pathway for cytosolic ferritin and cytosolic ferritin degradation is necessary for iron exit. In: Antioxidants and Redox Signaling. 2010 ; Vol. 13, No. 7. pp. 999-1009.
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