Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex i inhibitors

Distinct roles of superoxide anion and superoxide dismutases

Humberto Rodriguez-Rocha, Aracely Garcia-Garcia, Chillian Pickett, Sumin Li, Jocelyn Jones, Han Chen, Brian Webb, Jae Choi, You Zhou, Matthew C Zimmerman, Rodrigo Franco-Cruz

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)370-383
Number of pages14
JournalFree Radical Biology and Medicine
Volume61
DOIs
StatePublished - May 28 2013

Fingerprint

Oxidative stress
Cell death
Pesticides
Superoxides
Rotenone
Superoxide Dismutase
Paraquat
Oxidative Stress
Cell Death
Reactive Oxygen Species
Cytosol
Oxidation-Reduction
Antioxidant Response Elements
1-Methyl-4-phenylpyridinium
NF-kappa B
Mitochondrial Membrane Potential
Dopaminergic Neurons
Porphyrins
Electron Spin Resonance Spectroscopy
Manganese

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex i inhibitors : Distinct roles of superoxide anion and superoxide dismutases. / Rodriguez-Rocha, Humberto; Garcia-Garcia, Aracely; Pickett, Chillian; Li, Sumin; Jones, Jocelyn; Chen, Han; Webb, Brian; Choi, Jae; Zhou, You; Zimmerman, Matthew C; Franco-Cruz, Rodrigo.

In: Free Radical Biology and Medicine, Vol. 61, 28.05.2013, p. 370-383.

Research output: Contribution to journalArticle

Rodriguez-Rocha, Humberto ; Garcia-Garcia, Aracely ; Pickett, Chillian ; Li, Sumin ; Jones, Jocelyn ; Chen, Han ; Webb, Brian ; Choi, Jae ; Zhou, You ; Zimmerman, Matthew C ; Franco-Cruz, Rodrigo. / Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex i inhibitors : Distinct roles of superoxide anion and superoxide dismutases. In: Free Radical Biology and Medicine. 2013 ; Vol. 61. pp. 370-383.
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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.",
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