Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease

Bobby Thomas, Rebecca Banerjee, Natalia N. Starkova, Steven F. Zhang, Noel Y. Calingasan, Lichuan Yang, Elizabeth Wille, Beverly J. Lorenzo, Daniel J. Ho, M. Flint Beal, Anatoly Starkov

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Aims: Mitochondrial damage due to Ca 2+ overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca 2+ threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Results: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Innovation: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Conclusion: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.

Original languageEnglish (US)
Pages (from-to)855-868
Number of pages14
JournalAntioxidants and Redox Signaling
Volume16
Issue number9
DOIs
StatePublished - May 1 2012

Fingerprint

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinson Disease
Mitochondria
Knockout Mice
Permeability
1-Methyl-4-phenylpyridinium
Electron Transport Complex I
Dopaminergic Neurons
Mitochondrial Proteins
Depolarization
Cell death
Respiratory Rate
Electron Transport
Mesencephalon
Ablation
cyclophilin D
mitochondrial permeability transition pore
Neurons
Free Radicals
Brain

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. / Thomas, Bobby; Banerjee, Rebecca; Starkova, Natalia N.; Zhang, Steven F.; Calingasan, Noel Y.; Yang, Lichuan; Wille, Elizabeth; Lorenzo, Beverly J.; Ho, Daniel J.; Beal, M. Flint; Starkov, Anatoly.

In: Antioxidants and Redox Signaling, Vol. 16, No. 9, 01.05.2012, p. 855-868.

Research output: Contribution to journalArticle

Thomas, B, Banerjee, R, Starkova, NN, Zhang, SF, Calingasan, NY, Yang, L, Wille, E, Lorenzo, BJ, Ho, DJ, Beal, MF & Starkov, A 2012, 'Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease', Antioxidants and Redox Signaling, vol. 16, no. 9, pp. 855-868. https://doi.org/10.1089/ars.2010.3849
Thomas, Bobby ; Banerjee, Rebecca ; Starkova, Natalia N. ; Zhang, Steven F. ; Calingasan, Noel Y. ; Yang, Lichuan ; Wille, Elizabeth ; Lorenzo, Beverly J. ; Ho, Daniel J. ; Beal, M. Flint ; Starkov, Anatoly. / Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease. In: Antioxidants and Redox Signaling. 2012 ; Vol. 16, No. 9. pp. 855-868.
@article{235559623bb045c689e688c0411addbe,
title = "Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease",
abstract = "Aims: Mitochondrial damage due to Ca 2+ overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca 2+ threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Results: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Innovation: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Conclusion: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.",
author = "Bobby Thomas and Rebecca Banerjee and Starkova, {Natalia N.} and Zhang, {Steven F.} and Calingasan, {Noel Y.} and Lichuan Yang and Elizabeth Wille and Lorenzo, {Beverly J.} and Ho, {Daniel J.} and Beal, {M. Flint} and Anatoly Starkov",
year = "2012",
month = "5",
day = "1",
doi = "10.1089/ars.2010.3849",
language = "English (US)",
volume = "16",
pages = "855--868",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "9",

}

TY - JOUR

T1 - Mitochondrial permeability transition pore component cyclophilin D distinguishes nigrostriatal dopaminergic death paradigms in the MPTP mouse model of Parkinson's disease

AU - Thomas, Bobby

AU - Banerjee, Rebecca

AU - Starkova, Natalia N.

AU - Zhang, Steven F.

AU - Calingasan, Noel Y.

AU - Yang, Lichuan

AU - Wille, Elizabeth

AU - Lorenzo, Beverly J.

AU - Ho, Daniel J.

AU - Beal, M. Flint

AU - Starkov, Anatoly

PY - 2012/5/1

Y1 - 2012/5/1

N2 - Aims: Mitochondrial damage due to Ca 2+ overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca 2+ threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Results: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Innovation: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Conclusion: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.

AB - Aims: Mitochondrial damage due to Ca 2+ overload-induced opening of permeability transition pores (PTP) is believed to play a role in selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Genetic ablation of mitochondrial matrix protein cyclophilin D (CYPD) has been shown to increase Ca 2+ threshold of PTP in vitro and to prevent cell death in several in vivo disease models. We investigated the role of CYPD in a mouse model of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Results: We demonstrate that in vitro, brain mitochondria isolated from CYPD knockout mice were less sensitive to MPP+ (1-methyl-4-phenyl-pyridinium ion)-induced membrane depolarization, and free radical generation compared to wild-type mice. CYPD knockout mitochondria isolated from ventral midbrain of mice treated with MPTP in vivo exhibited less damage as judged from respiratory chain Complex I activity, State 3 respiration rate, and respiratory control index than wild-type mice, whereas assessment of apoptotic markers showed no differences between the two genotypes. However, CYPD knockout mice were significantly resistant only to an acute regimen of MPTP neurotoxicity in contrast to the subacute and chronic MPTP paradigms. Innovation: Inactivation of CYPD is beneficial in preserving mitochondrial functions only in an acute insult model of MPTP-induced dopaminergic neurotoxicity. Conclusion: Our results suggest that CYPD deficiency distinguishes the modes of dopaminergic neurodegeneration in various regimens of MPTP-neurotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=84863229879&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863229879&partnerID=8YFLogxK

U2 - 10.1089/ars.2010.3849

DO - 10.1089/ars.2010.3849

M3 - Article

C2 - 21529244

AN - SCOPUS:84863229879

VL - 16

SP - 855

EP - 868

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 9

ER -