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Title | Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability |
Creator | Huang, Chuen-Lin;Chao, Chih-Chang;Lee, Yi-Chao;Lu, Mei-Kuang;Cheng, Jing-Jy;Yang, Ying-Chen;Wang, Vin-Chi;Chang, Wen-Chang;Huang, Nai-Kuei 趙知章 |
Contributor | 神經科學研究所 |
Key Words | Mitochondrial membrane permeability;Mitochondrial permeability transition pores;Mitochondrial apoptosis-induced channels;Paraquat;Parkinson’s disease |
Date | 2015-05 |
Date Issued | 5-Aug-2015 14:11:05 (UTC+8) |
Summary | Paraquat (PQ) as a Parkinsonian mimetic has been demonstrated to impair dopaminergic (DAergic) neurons and is highly correlated with the etiology of Parkinson’s disease (PD) where the death of DAergic neurons has been mainly attributed to impaired mitochondrial functioning. In this study, PQ-induced cytotoxicity focusing on mitochondrial membrane permeability (MMP), which has been implicated to play a part in neurodegeneration, was investigated. Primarily, PQ-induced cytotoxicity and reactive oxygen species (ROS) were inhibited by an inhibitor of NADPH oxidase (NOX), indicating the toxic effect of PQ redox cycling. Further, dibucaine and cyclosporin A which respectively inhibit mitochondrial apoptosis-induced channels (MAC) and mitochondrial permeability transition pores (mPTP) were used and found to prevent PQ-induced mitochondrial dysfunction, such as decreased mitochondrial membrane potential and increased MMP, mitochondrial ROS, and pro-apoptotic factor release. Knockdown of bax and/or bak blocked PQ-induced mitochondrial clusterization of Bax and/or Bak and cytotoxicity, demonstrating the significance of MAC which is composed of Bax and/or Bak. This clusterization coincided with the release of mitochondrial apoptotic factors before there was an increase in inner MMP, indicating that MAC may precede mPTP formation. Besides, NOX inhibitor but not dibucaine attenuated the earlier PQ-induced cytosolic ROS formation or Bax and/or Bak clusterization indicating PQ redox cycling may account for MAC formation. In this model, we have resolved for the first that PQ cytotoxicity through redox cycling may sequentially result in increased outer (MAC) and inner (mPTP) MMP and suggested MMP could be implicated as a therapeutic target in treating neurodegenerative diseases like PD. |
Relation | Molecular Neurobiology |
Type | article |
DOI | http://dx.doi.org/10.1007/s12035-015-9198-y |
dc.contributor | 神經科學研究所 | |
dc.creator (作者) | Huang, Chuen-Lin;Chao, Chih-Chang;Lee, Yi-Chao;Lu, Mei-Kuang;Cheng, Jing-Jy;Yang, Ying-Chen;Wang, Vin-Chi;Chang, Wen-Chang;Huang, Nai-Kuei | |
dc.creator (作者) | 趙知章 | zh_TW |
dc.date (日期) | 2015-05 | |
dc.date.accessioned | 5-Aug-2015 14:11:05 (UTC+8) | - |
dc.date.available | 5-Aug-2015 14:11:05 (UTC+8) | - |
dc.date.issued (上傳時間) | 5-Aug-2015 14:11:05 (UTC+8) | - |
dc.identifier.uri (URI) | http://nccur.lib.nccu.edu.tw/handle/140.119/77406 | - |
dc.description.abstract (摘要) | Paraquat (PQ) as a Parkinsonian mimetic has been demonstrated to impair dopaminergic (DAergic) neurons and is highly correlated with the etiology of Parkinson’s disease (PD) where the death of DAergic neurons has been mainly attributed to impaired mitochondrial functioning. In this study, PQ-induced cytotoxicity focusing on mitochondrial membrane permeability (MMP), which has been implicated to play a part in neurodegeneration, was investigated. Primarily, PQ-induced cytotoxicity and reactive oxygen species (ROS) were inhibited by an inhibitor of NADPH oxidase (NOX), indicating the toxic effect of PQ redox cycling. Further, dibucaine and cyclosporin A which respectively inhibit mitochondrial apoptosis-induced channels (MAC) and mitochondrial permeability transition pores (mPTP) were used and found to prevent PQ-induced mitochondrial dysfunction, such as decreased mitochondrial membrane potential and increased MMP, mitochondrial ROS, and pro-apoptotic factor release. Knockdown of bax and/or bak blocked PQ-induced mitochondrial clusterization of Bax and/or Bak and cytotoxicity, demonstrating the significance of MAC which is composed of Bax and/or Bak. This clusterization coincided with the release of mitochondrial apoptotic factors before there was an increase in inner MMP, indicating that MAC may precede mPTP formation. Besides, NOX inhibitor but not dibucaine attenuated the earlier PQ-induced cytosolic ROS formation or Bax and/or Bak clusterization indicating PQ redox cycling may account for MAC formation. In this model, we have resolved for the first that PQ cytotoxicity through redox cycling may sequentially result in increased outer (MAC) and inner (mPTP) MMP and suggested MMP could be implicated as a therapeutic target in treating neurodegenerative diseases like PD. | |
dc.format.extent | 8382743 bytes | - |
dc.format.mimetype | application/pdf | - |
dc.relation (關聯) | Molecular Neurobiology | |
dc.subject (關鍵詞) | Mitochondrial membrane permeability;Mitochondrial permeability transition pores;Mitochondrial apoptosis-induced channels;Paraquat;Parkinson’s disease | |
dc.title (題名) | Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability | |
dc.type (資料類型) | article | en |
dc.identifier.doi (DOI) | 10.1007/s12035-015-9198-y | |
dc.doi.uri (DOI) | http://dx.doi.org/10.1007/s12035-015-9198-y |