TY - JOUR
T1 - Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex i inhibitors
T2 - Distinct roles of superoxide anion and superoxide dismutases
AU - Rodriguez-Rocha, Humberto
AU - Garcia-Garcia, Aracely
AU - Pickett, Chillian
AU - Li, Sumin
AU - Jones, Jocelyn
AU - Chen, Han
AU - Webb, Brian
AU - Choi, Jae
AU - Zhou, You
AU - Zimmerman, Matthew C.
AU - Franco, Rodrigo
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant P20RR17675 Centers of Biomedical Research Excellence (COBRE) (Franco and Zimmerman) , R01 HL103942 (Zimmerman), the Research Council Interdisciplinary Grant, and the Life Sciences Grant Program of the University of Nebraska–Lincoln (Franco). We thank Dr. Charles A. Kuszynski, Daniel Shea, and Zhi Hong Gill at the Nebraska Center for Virology for their help in the flow cytometry analyses and cell sorting, as well as Terri Fangman at the Morrison Microscopy Core Research Facility for her help in the confocal microscopy analyses.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - CuZnSOD
KW - Environmental
KW - MPP+
KW - MnSOD
KW - Paraquat
KW - Parkinson's disease
KW - Pesticides
KW - Porphyrins
KW - Rotenone
KW - SOD
KW - roGFP
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UR - http://www.scopus.com/inward/citedby.url?scp=84878005048&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2013.04.021
DO - 10.1016/j.freeradbiomed.2013.04.021
M3 - Article
C2 - 23602909
AN - SCOPUS:84878005048
SN - 0891-5849
VL - 61
SP - 370
EP - 383
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -