PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons

Hung Li Wang, An Hsun Chou, Ai Shun Wu, Si Ying Chen, Yi Hsin Weng, Yu Cheng Kao, Tu Hsueh Yeh, Po Ju Chu, Chin Song Lu

Research output: Contribution to journalArticle

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Abstract

Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). PINK1 is believed to exert neuroprotective effect on SN dopaminergic cells by acting as a mitochondrial Ser/Thr protein kinase. Autosomal recessive inheritance indicates the involvement of loss of PINK1 function in PARK6 pathogenesis. In the present study, confocal imaging of cultured SN dopaminergic neurons prepared from PINK1 knockout mice was performed to investigate physiological importance of PINK1 in maintaining mitochondrial membrane potential (δΨm) and mitochondrial morphology and test the hypothesis that PARK6 mutations cause the loss of PINK1 function. PINK1-deficient SN dopaminergic neurons exhibited a depolarized δΨm. In contrast to long thread-like mitochondria of wild-type neurons, fragmented mitochondria were observed from PINK1-null SN dopaminergic cells. Basal level of mitochondrial superoxide and oxidative stressor H2O2-induced ROS generation were significantly increased in PINK1-deficient dopaminergic neurons. Overexpression of wild-type PINK1 restored hyperpolarized δΨm and thread-like mitochondrial morphology and inhibited ROS formation in PINK1-null dopaminergic cells. PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-deficient dopaminergic neurons. Mitochondrial toxin rotenone-induced cell death of dopaminergic neurons was augmented in PINK1-null SN neuronal culture. These results indicate that PINK1 is required for maintaining normal δΨm and mitochondrial morphology of cultured SN dopaminergic neurons and exerts its neuroprotective effect by inhibiting ROS formation. Our study also provides the evidence that PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 is defective in regulating mitochondrial functions and attenuating ROS production of SN dopaminergic cells.

Original languageEnglish
Pages (from-to)674-684
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1812
Issue number6
DOIs
Publication statusPublished - Jun 2011
Externally publishedYes

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Mitochondrial Membrane Potential
Dopaminergic Neurons
Substantia Nigra
Phosphotransferases
Neuroprotective Agents
Mitochondria
Recessive Genes
Rotenone
Null Lymphocytes
Mutation
Knockout Mice
Superoxides
Protein Kinases

Keywords

  • Mitochondrial fragmentation
  • Mitochondrial membrane potential
  • Parkinson's disease
  • PTEN-induced kinase 1
  • Reactive oxygen species
  • Substantia nigra dopaminergic neuron

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. / Wang, Hung Li; Chou, An Hsun; Wu, Ai Shun; Chen, Si Ying; Weng, Yi Hsin; Kao, Yu Cheng; Yeh, Tu Hsueh; Chu, Po Ju; Lu, Chin Song.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1812, No. 6, 06.2011, p. 674-684.

Research output: Contribution to journalArticle

Wang, Hung Li ; Chou, An Hsun ; Wu, Ai Shun ; Chen, Si Ying ; Weng, Yi Hsin ; Kao, Yu Cheng ; Yeh, Tu Hsueh ; Chu, Po Ju ; Lu, Chin Song. / PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2011 ; Vol. 1812, No. 6. pp. 674-684.
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abstract = "Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). PINK1 is believed to exert neuroprotective effect on SN dopaminergic cells by acting as a mitochondrial Ser/Thr protein kinase. Autosomal recessive inheritance indicates the involvement of loss of PINK1 function in PARK6 pathogenesis. In the present study, confocal imaging of cultured SN dopaminergic neurons prepared from PINK1 knockout mice was performed to investigate physiological importance of PINK1 in maintaining mitochondrial membrane potential (δΨm) and mitochondrial morphology and test the hypothesis that PARK6 mutations cause the loss of PINK1 function. PINK1-deficient SN dopaminergic neurons exhibited a depolarized δΨm. In contrast to long thread-like mitochondria of wild-type neurons, fragmented mitochondria were observed from PINK1-null SN dopaminergic cells. Basal level of mitochondrial superoxide and oxidative stressor H2O2-induced ROS generation were significantly increased in PINK1-deficient dopaminergic neurons. Overexpression of wild-type PINK1 restored hyperpolarized δΨm and thread-like mitochondrial morphology and inhibited ROS formation in PINK1-null dopaminergic cells. PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-deficient dopaminergic neurons. Mitochondrial toxin rotenone-induced cell death of dopaminergic neurons was augmented in PINK1-null SN neuronal culture. These results indicate that PINK1 is required for maintaining normal δΨm and mitochondrial morphology of cultured SN dopaminergic neurons and exerts its neuroprotective effect by inhibiting ROS formation. Our study also provides the evidence that PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 is defective in regulating mitochondrial functions and attenuating ROS production of SN dopaminergic cells.",
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AU - Wang, Hung Li

AU - Chou, An Hsun

AU - Wu, Ai Shun

AU - Chen, Si Ying

AU - Weng, Yi Hsin

AU - Kao, Yu Cheng

AU - Yeh, Tu Hsueh

AU - Chu, Po Ju

AU - Lu, Chin Song

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AB - Mutations in PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson's disease (PARK6). PINK1 is believed to exert neuroprotective effect on SN dopaminergic cells by acting as a mitochondrial Ser/Thr protein kinase. Autosomal recessive inheritance indicates the involvement of loss of PINK1 function in PARK6 pathogenesis. In the present study, confocal imaging of cultured SN dopaminergic neurons prepared from PINK1 knockout mice was performed to investigate physiological importance of PINK1 in maintaining mitochondrial membrane potential (δΨm) and mitochondrial morphology and test the hypothesis that PARK6 mutations cause the loss of PINK1 function. PINK1-deficient SN dopaminergic neurons exhibited a depolarized δΨm. In contrast to long thread-like mitochondria of wild-type neurons, fragmented mitochondria were observed from PINK1-null SN dopaminergic cells. Basal level of mitochondrial superoxide and oxidative stressor H2O2-induced ROS generation were significantly increased in PINK1-deficient dopaminergic neurons. Overexpression of wild-type PINK1 restored hyperpolarized δΨm and thread-like mitochondrial morphology and inhibited ROS formation in PINK1-null dopaminergic cells. PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-deficient dopaminergic neurons. Mitochondrial toxin rotenone-induced cell death of dopaminergic neurons was augmented in PINK1-null SN neuronal culture. These results indicate that PINK1 is required for maintaining normal δΨm and mitochondrial morphology of cultured SN dopaminergic neurons and exerts its neuroprotective effect by inhibiting ROS formation. Our study also provides the evidence that PARK6 mutant (G309D), (E417G) or (Cδ145) PINK1 is defective in regulating mitochondrial functions and attenuating ROS production of SN dopaminergic cells.

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KW - PTEN-induced kinase 1

KW - Reactive oxygen species

KW - Substantia nigra dopaminergic neuron

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