Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis.
Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis.
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DOI：
10.1371/journal.pone.0091848
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kotler ML
中科院分区：
文献类型：
--
作者：
Alaimo A;Gorojod RM;Beauquis J;Muñoz MJ;Saravia F;Kotler ML
线粒体是动态的细胞器，经历融合和分裂过程。这些事件是由神经纤维形成蛋白调节的。这些蛋白质的表达和/或定位的变化导致线粒体动力学损伤，并可能促进细胞凋亡。越来越多的证据表明，线粒体动力学破坏与神经退行性疾病的发生有关。因此，我们专注于锰（Mn）诱导的帕金森病，与锰积累优先在基底神经节，其中来自星形胶质细胞的线粒体代表早期目标的障碍。使用MitoTracker Red染色，我们观察到锰暴露的大鼠星形细胞瘤C6细胞中线粒体网络分裂增加。此外，锰诱导融合蛋白Opa-1水平的显着下降，以及裂变蛋白Drp-1的表达显着增加。此外，锰引起高分子量Opa-1亚型从线粒体到胞质溶胶的显著释放以及增加Drp-1向线粒体的易位。药物Drp-1抑制剂Mdivi-1和大鼠Drp-1 siRNA均减少了凋亡细胞核的数量，保持了线粒体网络的完整性并防止了细胞死亡。CsA是一种MPTP开放抑制剂，可阻止线粒体Δ m的破坏、Opa-1的加工和Drp-1向线粒体的转位，从而保护Mn暴露的细胞免受线粒体破坏和凋亡。组织学分析和Hoechst 33258染色的脑切片的Mn注射大鼠在纹状体中表现出减少的细胞质量的凋亡细胞核的发生率增加。Mn处理也改变了Opa-1和Drp-1的表达水平。我们的研究结果首次表明，异常的线粒体动力学在体外和体内锰毒性。此外，我们表明，融合/裂变平衡的不平衡可能参与锰诱导的细胞凋亡。这些知识可能为锰中毒和其他神经退行性疾病的治疗提供新的治疗工具。
Mitochondria are dynamic organelles that undergo fusion and fission processes. These events are regulated by mitochondria-shaping proteins. Changes in the expression and/or localization of these proteins lead to a mitochondrial dynamics impairment and may promote apoptosis. Increasing evidence correlates the mitochondrial dynamics disruption with the occurrence of neurodegenerative diseases. Therefore, we focused on this topic in Manganese (Mn)-induced Parkinsonism, a disorder associated with Mn accumulation preferentially in the basal ganglia where mitochondria from astrocytes represent an early target. Using MitoTracker Red staining we observed increased mitochondrial network fission in Mn-exposed rat astrocytoma C6 cells. Moreover, Mn induced a marked decrease in fusion protein Opa-1 levels as well as a dramatic increase in the expression of fission protein Drp-1. Additionally, Mn provoked a significant release of high MW Opa-1 isoforms from the mitochondria to the cytosol as well as an increased Drp-1 translocation to the mitochondria. Both Mdivi-1, a pharmacological Drp-1 inhibitor, and rat Drp-1 siRNA reduced the number of apoptotic nuclei, preserved the mitochondrial network integrity and prevented cell death. CsA, an MPTP opening inhibitor, prevented mitochondrial Δψm disruption, Opa-1 processing and Drp-1 translocation to the mitochondria therefore protecting Mn-exposed cells from mitochondrial disruption and apoptosis. The histological analysis and Hoechst 33258 staining of brain sections of Mn-injected rats in the striatum showed a decrease in cellular mass paralleled with an increase in the occurrence of apoptotic nuclei. Opa-1 and Drp-1 expression levels were also changed by Mn-treatment. Our results demonstrate for the first time that abnormal mitochondrial dynamics is implicated in both in vitro and in vivo Mn toxicity. In addition we show that the imbalance in fusion/fission equilibrium might be involved in Mn-induced apoptosis. This knowledge may provide new therapeutic tools for the treatment of Manganism and other neurodegenerative diseases.
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影响因子：
3.7
作者：
Galli S;Jahn O;Hitt R;Hesse D;Opitz L;Plessmann U;Urlaub H;Poderoso JJ;Jares-Erijman EA;Jovin TM
通讯作者：
Jovin TM
影响因子：
7.4
作者：
Gomez-Lazaro, Maria;Bonekamp, Nina A.;Schrader, Michael
通讯作者：
Schrader, Michael
影响因子：
4.4
作者：
Ganapathy, Preethi S.;Perry, Richard L.;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
影响因子：
4.2
作者：
Gonzalez, Laura E.;Juknat, A. Ana;Kotler, Monica L.
通讯作者：
Kotler, Monica L.