Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability

Chuen Lin Huang, Chih Chang Chao, Yi Chao Lee, Mei Kuang Lu, Jing Jy Cheng, Ying Chen Yang, Vin Chi Wang, Wen Chang Chang, Nai Kuei Huang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalMolecular Neurobiology
DOIs
Publication statusPublished - 2016

Fingerprint

Paraquat
Mitochondrial Membranes
Permeability
Cell Death
Apoptosis
Dibucaine
Oxidation-Reduction
Reactive Oxygen Species
NADPH Oxidase
Dopaminergic Neurons
Parkinson Disease
Mitochondrial Membrane Potential
Poisons
Neurodegenerative Diseases
Cyclosporine

Keywords

  • Mitochondrial apoptosis-induced channels
  • Mitochondrial membrane permeability
  • Mitochondrial permeability transition pores
  • Paraquat
  • Parkinson’s disease

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability. / 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.

In: Molecular Neurobiology, 2016.

Research output: Contribution to journalArticle

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. / Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability. In: Molecular Neurobiology. 2016.
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abstract = "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.",
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