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Free Radic Biol Med. 2013 Aug;61:370-83. doi: 10.1016/j.freeradbiomed.2013.04.021. Epub 2013 Apr 19.

Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex I inhibitors: distinct roles of superoxide anion and superoxide dismutases.

Author information

  • 1Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA.
  • 2Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
  • 3Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA.
  • 4Thermo Scientific, Research and Development, Rockford, IL 61105, USA.
  • 5Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA; Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA.
  • 6Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
  • 7Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA; School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0905, USA. Electronic address: rfrancocruz2@unl.edu.

Abstract

The loss of dopaminergic neurons induced by the parkinsonian toxins paraquat, rotenone, and 1-methyl-4-phenylpyridinium (MPP(+)) is associated with oxidative stress. However, controversial reports exist regarding the source/compartmentalization of reactive oxygen species (ROS) generation and its exact role in cell death. We aimed to determine in detail the role of superoxide anion (O2(•-)), oxidative stress, and their subcellular compartmentalization in dopaminergic cell death induced by parkinsonian toxins. Oxidative stress and ROS formation were determined in the cytosol, intermembrane (IMS), and mitochondrial matrix compartments, using dihydroethidine derivatives and the redox sensor roGFP, as well as electron paramagnetic resonance spectroscopy. Paraquat induced an increase in ROS and oxidative stress in both the cytosol and the mitochondrial matrix prior to cell death. MPP(+) and rotenone primarily induced an increase in ROS and oxidative stress in the mitochondrial matrix. No oxidative stress was detected at the level of the IMS. In contrast to previous studies, overexpression of manganese superoxide dismutase (MnSOD) or copper/zinc SOD (CuZnSOD) had no effect on alterations in ROS steady-state levels, lipid peroxidation, loss of mitochondrial membrane potential (ΔΨm), and dopaminergic cell death induced by MPP(+) or rotenone. In contrast, paraquat-induced oxidative stress and cell death were selectively reduced by MnSOD overexpression, but not by CuZnSOD or manganese-porphyrins. However, MnSOD also failed to prevent ΔΨm loss. Finally, paraquat, but not MPP(+) or rotenone, induced the transcriptional activation of the redox-sensitive antioxidant response elements (ARE) and nuclear factor kappa-B (NF-κB). These results demonstrate a selective role of mitochondrial O2(•-) in dopaminergic cell death induced by paraquat, and show that toxicity induced by the complex I inhibitors rotenone and MPP(+) does not depend directly on mitochondrial O2(•-) formation.

Copyright © 2013 Elsevier Inc. All rights reserved.

KEYWORDS:

CuZnSOD; Environmental; MPP+; MnSOD; Paraquat; Parkinson's disease; Pesticides; Porphyrins; Rotenone; SOD; roGFP

PMID:
23602909
[PubMed - indexed for MEDLINE]
PMCID:
PMC3883883
Free PMC Article
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