3-Nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells

Bhaskar S. Mandavilli, Istvan Boldogh, Bennett Van Houten

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

3-Nitropropionic acid (3-NPA), a complex II inhibitor of the electron transport chain, causes Huntington disease-like symptoms after administration into animals. However, primary mechanisms of cell death are not clearly understood. This study tested the hypothesis that 3-NPA leads to the generation of reactive oxygen species (ROS), mitochondrial DNA damage, and loss of mitochondrial function. Amplex red and horseradish peroxidase were used to accurately measure the amount of H2O2, and showed that PC12 cells treated with 3-NPA (4 mM) lead to the production of hydrogen peroxide (1 nmol/106 cells/h). This amount of 3-NPA also leads to a rapid decline of ATP levels. There was time- and dose-dependent mitochondrial DNA damage following 3-NPA treatment. Overexpression of the proto-oncogene bcl-2 protects cells from apoptosis induced by various stimuli. Overexpression of Bcl-2 leads to almost threefold higher levels of ATP and also decreased the 3-NPA-mediated induction of hydrogen peroxide by over 50%. Bcl-2-overexpressing PC12 cells were also protected from mitochondrial DNA damage. These data show that ROS production followed by mitochondrial DNA damage is the primary event in 3-NPA toxicity, and Bcl-2 protects PC12 cells from 3-NPA toxicity by preventing mitochondrial DNA damage.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
JournalMolecular Brain Research
Volume133
Issue number2
DOIs
StatePublished - Feb 18 2005

Fingerprint

PC12 Cells
Mitochondrial DNA
Hydrogen Peroxide
DNA Damage
Cell Death
Reactive Oxygen Species
Electron Transport Complex II
Adenosine Triphosphate
Proto-Oncogenes
3-nitropropionic acid
Huntington Disease
Horseradish Peroxidase
Apoptosis

Keywords

  • 3-Nitropropionic acid
  • Bcl-2
  • Huntington's disease
  • Mitochondrial DNA
  • Neurotoxicity
  • PC12 cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

3-Nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. / Mandavilli, Bhaskar S.; Boldogh, Istvan; Van Houten, Bennett.

In: Molecular Brain Research, Vol. 133, No. 2, 18.02.2005, p. 215-223.

Research output: Contribution to journalArticle

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