Mitochondrial ferritin suppresses MPTP-induced cell damage by regulating iron metabolism and attenuating oxidative stress

Autor: Zhenhua Shi, Yan-Zhong Chang, Bao-Lu Zhao, Lin-hao You, Xianglin Duan, Zhen Li
Rok vydání: 2016
Předmět:
0301 basic medicine
1-Methyl-4-phenylpyridinium
Apoptosis
medicine.disease_cause
Hippocampus
Mice
chemistry.chemical_compound
0302 clinical medicine
Inner mitochondrial membrane
Cation Transport Proteins
Mice
Knockout
chemistry.chemical_classification
General Neuroscience
MPTP
Brain
Parkinson Disease
Mitochondria
Cell biology
Substantia Nigra
Biochemistry
Tyrosine 3-Monooxygenase
Cell Survival
Iron
Transferrin receptor
Substantia nigra
Biology
03 medical and health sciences
Receptors
Transferrin
medicine
Animals
Molecular Biology
Cell damage
Reactive oxygen species
Tyrosine hydroxylase
MPTP Poisoning
medicine.disease
Corpus Striatum
nervous system diseases
Disease Models
Animal
Oxidative Stress
030104 developmental biology
nervous system
chemistry
Apoferritins
Ferritins
Neurology (clinical)
Reactive Oxygen Species
030217 neurology & neurosurgery
Oxidative stress
Developmental Biology
Zdroj: Brain Research. 1642:33-42
ISSN: 0006-8993
DOI: 10.1016/j.brainres.2016.03.023
Popis: Our previous work showed that mitochondrial ferritin (MtFt) played an important role in preventing neuronal damage in 6-OHDA-induced Parkinson's disease (PD). However, the role of MtFt in a PD model induced by MPTP is not clear. Here, we found that methyl-4-phenyl-1, 2, 3, 6-tetra-pyridine (MPTP) significantly upregulated MtFt in the mouse hippocampus, substantia nigra (SN) and striatum. To explore the effect of MtFt upregulation on the MPTP-mediated injury to neural cells, MtFt-/- mice and MtFt-overexpressing cells were used to construct models of PD induced by MPTP. Our results showed that MPTP dramatically downregulated expression of transferrin receptor 1 (TfR1) and tyrosine hydroxylase and upregulated L-ferritin expression in the mouse striatum and SN. Interestingly, MPTP induced high levels of MtFt in these tissues, indicating that MtFt was involved in iron metabolism and influenced dopamine synthesis induced by MPTP. Meanwhile, the Bcl2/Bax ratio was decreased significantly by MPTP in the striatum and SN of MtFt knockout (MtFt-/-) mice compared with controls. Overexpression of MtFt increased TfR1 and decreased ferroportin 1 induced by 1-methyl-4-phenylpyridinium ions (MPP+). MtFt strongly inhibited mitochondrial damage through maintaining the mitochondrial membrane potential and protecting the integrity of the mitochondrial membrane. It also suppressed the increase of the labile iron pool, decreased production of reactive oxygen species and dramatically rescued the apoptosis induced by MPP+. In conclusion, this study demonstrates that MtFt plays an important role in preventing neuronal damage in the MPTP-induced parkinsonian phenotype by inhibiting cellular iron accumulation and subsequent oxidative stress.
Databáze: OpenAIRE
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