Mitochondrial ferritin protects SH-SY5Y cells against H2O2-induced oxidative stress and modulates α-synuclein expression.
Mitochondrial ferritin (FtMt) is a type of ferritin that sequesters iron. Previous studies have shown that FtMt is expressed by dopaminergic neurons in the substantia nigra and that it may be involved in the pathology of Parkinson's disease. However, the functional roles of FtMt in dopaminergic neurons remain unclear. In this study, we investigated the function of FtMt in α-synuclein regulation and its antioxidant roles in dopaminergic cells using human dopaminergic neuroblastoma cells, SH-SY5Y. In physiological conditions, FtMt knockdown increased α-synuclein expression at the protein level but not at the mRNA level. By contrast, FtMt overexpression reduced α-synuclein expression at the protein level but not at the mRNA level. FtMt enhanced the iron levels in mitochondria but decreased the iron levels in the intracellular labile iron pool. We found that FeCl2could abolish the effects of FtMt overexpression on α-synuclein expression. Under oxidative stress conditions induced by H2O2, we found that H2O2treatment induced FtMt and α-synuclein expression at both the mRNA and protein levels in a dose-dependent manner. FtMt overexpression protected cells against oxidative stress and alleviated the enhanced α-synuclein expression induced by H2O2at the posttranscriptional level. Our results indicate that FtMt modulates α-synuclein expression at the posttranscriptional level via iron regulation in physiological conditions. FtMt expression is enhanced under oxidative stress conditions, where FtMt protects cells against the oxidative stress as well as plays an important role in maintaining α-synuclein levels.
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan; Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Hongpeng
H
Guan
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan; Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Hongkuan
H
Yang
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan; Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Mingchun
M
Yang
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan.
Daijiro
D
Yanagisawa
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan.
Jean-Pierre
JP
Bellier
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan.
Masaki
M
Mori
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan.
Shogo
S
Takahata
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Takashi
T
Nonaka
Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin 150001, China. Electronic address: guangsz@hotmail.com.
Shiguang
S
Zhao
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan. Electronic address: kinchan@belle.shiga-med.ac.jp.
Ikuo
I
Tooyama
D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D005293:Ferritins / Q000378:metabolism*; D005296:Ferrous Compounds / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017262:Siderophores / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D005296:Ferrous Compounds; D024101:Mitochondrial Proteins; D017262:Siderophores; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D005293:Ferritins; D006861:Hydrogen Peroxide; D007501:Iron; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D003676:Deferoxamine; C029451:ferrous chloride
Iron; Mitochondrial ferritin; Oxidative stress; Parkinson's disease; α-Synuclein