Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis has been identified as one of the important mechanisms involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Our previous study showed increased iron levels in the substantia nigra as well as loss of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse models. 1-Methyl-4-phenylpyridinium (MPP(+)) is commonly used to establish a cellular model of PD. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular mechanism linking increased iron and MPP(+)-induced neurodegeneration is largely unknown. In the present study, we investigate the involvement of divalent metal transporter 1 (DMT1) that accounts for the ferrous iron transport in MPP(+)-treated MES23.5 cells. In the treated cells, a significant influx of ferrous iron was observed. This resulted in a decreased mitochondrial membrane potential. Additionally, an elevated level of ROS production and activation of caspase-3 were also detected, as well as the subsequent cell apoptosis. These effects could be fully abolished by iron chelator desferal (DFO). Increased DMT1 (-IRE) expression but not DMT1 (+IRE) accounted for the increased iron influx. However, there were no changes for iron regulatory protein 1 (IRP1), despite decreased expression of IRP2. Iron itself had no effect on IRP1 and IRP2 expression. Our data suggest that although DMT1 mRNA contains an iron responsive element, its expression is not totally controlled by this. MPP(+) could up-regulate the expression of DMT1 (-IRE) in an IRE/IRP-independent manner. Our findings also show that MPP(+)-induced apoptosis in MES23.5 cells involves DMT1-dependent iron influx and mitochondria dysfunction.
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PMID:Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. 1819 77

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1 alpha can be stimulated via oxygen (O(2))-independent mechanisms; whereas, the degradation of HIF-1 alpha is regulated via Fe(2+) and/or O(2)-dependent enzyme prolyl hydroxylase (PHD). Aberrant iron accumulation, mitochondrial dysfunction and impairment of protein degradation system, such as autophagy, have been implicated in the pathogenesis of Parkinson's disease, among which, iron and mitochondrial dysfunction may enhance the enzyme activity of prolyl hydroxylase and cause the decrease of HIF-1 alpha. Recent reports have indicated that HIF-1 alpha may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1 alpha under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1 alpha could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1 alpha due to the decreased degradation of HIF-1 alpha via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1 alpha was decreased in rotenone or MPP(+)-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1 alpha accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1 alpha gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1 alpha. Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1 alpha or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1 alpha was decreased under the situation when mitochondrial complex I was inhibited, and the neuroprotective role of deferoxamine in rotenone-induced apoptosis could be partially explained by its effects on the accumulation of HIF-1 alpha and HIF-1 alpha-mediated induction of autophagy.
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PMID:Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells. 2054 14