Divalent metal transporter, iron, and Parkinson's disease: A pathological relationship

AbstractAs a novel discovered regulated cell death pattern, ferroptosis has been associated with the development of Parkinson’s disease (PD) and has attracted widespread attention. Nevertheless, the relationship between ferroptosis and PD pathogenesis is still unclear. This study aims to investigate the effect of iron overload on dopaminergic (DA) neurons and its correlation with ferroptosis. Here we use nerve growth factor (NGF) induced PC12 cells which are derived from pheochromocytoma of the rat adrenal to establish a classical PD in vitro model. We found significantly decreased cell viability in NGF-PC12 cell under ammonium ferric citrate (FAC) administration. Moreover, excessive intracellular iron ions induced the increase of (reactive oxygen species) ROS release as well as the decrease of mitochondrial membrane potential in PC12-NGF cells. In addition, we also found that overloaded iron can activate cell apoptosis and ferroptosis pathways, which led to cell death. Furthermore, MPP-induced PD cells were characterized by mitochondrial shrinkage, decreased expression of glutathione peroxidase 4 (Gpx4) and ferritin heavy chain (FTH1), and increased divalent metal transporter (DMT1) and transferrin receptor 1 (TfR1) expression level. In contrast, Lip-1 and DFO increased the expression level of GPX4 and FTH1 compared to MPP-induced PD cell. In conclusion, we indicated that overloaded intracellular iron contributes to neurons death via apoptosis and ferroptosis pathways, while DFO, an iron chelator, can inhibit ferroptosis in order to protect the neurons in vitro.

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Hypoxia induces changes in expression of isoforms of the divalent metal transporter (DMT1) in rat pheochromocytoma (PC12) cells

Biochemical Pharmacology ◽

10.1016/j.bcp.2005.03.023 ◽

2005 ◽

Vol 69 (11) ◽

pp. 1647-1655 ◽

Cited By ~ 34

Author(s):

Agnieszka Lis ◽

Prasad N. Paradkar ◽

Steve Singleton ◽

Hung-Chieh Kuo ◽

Michael D. Garrick ◽

...

Keyword(s):

Pc12 Cells ◽

Divalent Metal ◽

Divalent Metal Transporter ◽

Metal Transporter ◽

Pheochromocytoma Pc12 ◽

Pheochromocytoma Pc12 Cells

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Divalent Metal Transporter 1 Knock-Down Modulates IL-1β Mediated Pancreatic Beta-Cell Pro-Apoptotic Signaling Pathways through the Autophagic Machinery

International Journal of Molecular Sciences ◽

10.3390/ijms22158013 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8013

Author(s):

Taewook Kang ◽

Honggang Huang ◽

Thomas Mandrup-Poulsen ◽

Martin R. Larsen

Keyword(s):

Cell Death ◽

Divalent Metal ◽

Β Cells ◽

Β Cell ◽

Divalent Metal Transporter 1 ◽

Divalent Metal Transporter ◽

Knock Down ◽

Metal Transporter ◽

Cell Functions ◽

Protective Proteins

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.

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