Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease.
Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly down-regulated via doxycycline induction of antisense messages against both the heavy and light subunits of gamma-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione synthesis. Down-regulation of glutamyl-cysteine synthetase results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be because of a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.
Jha
N
N
Division of Neurogerontology, Andrus Gerontology Center and Programs in Neurobiology and Molecular Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
Jurma
O
O
Lalli
G
G
Liu
Y
Y
Pettus
E H
EH
Greenamyre
J T
JT
Liu
R M
RM
Forman
H J
HJ
Andersen
J K
JK
D000818:Animals; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D042967:Electron Transport Complex I; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D005978:Glutathione; D004318:Doxycycline; D019803:Glutathione Disulfide