title: Mitochondrial ferritin suppresses MPTP-induced cell damage by regulating iron metabolism and attenuating oxidative stress.
abstract: 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.
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China.
authors.forename: Lin-Hao
authors.initials: LH
authors.lastname: You
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China.
authors.forename: Xiang-Lin
authors.initials: XL
authors.lastname: Duan
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China.
authors.forename: Bao-Lu
authors.initials: BL
authors.lastname: Zhao
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China. Electronic address: shizhhtom@126.com.
authors.forename: Yan-Zhong
authors.initials: YZ
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050016, Hebei Province, China. Electronic address: frankyzchang@yahoo.com.hk.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Shi
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage; D000818:Animals; D001052:Apoferritins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium
keywords: Apoptosis; Iron metabolism; MPTP; Mitochondrial ferritin; Parkinson’s disease