Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson's disease: a dynamic model.
Oxidative/nitrosative stress and mitochondrial dysfunction have been implicated in the degeneration of dopaminergic neurons in the substantia nigra during Parkinson's disease (PD). During early stages of PD, there is a significant depletion of the thiol antioxidant glutathione (GSH), which may lead to oxidative stress, mitochondrial dysfunction, and ultimately neuronal cell death. Mitochondrial complex I (CI) is believed to be the central player to the mitochondrial dysfunction occurring in PD. We have generated a dynamic, mechanistic model for mitochondrial dysfunction associated with PD progression that is activated by rotenone, GSH depletion, increased nitric oxide and peroxynitrite. The potential insults independently inhibit CI and other complexes of the electron transport chain, drop the proton motive force, and reduce ATP production, ultimately affecting the overall mitochondrial performance. We show that mitochondrial dysfunction significantly affects glutathione synthesis thereby increasing the oxidative damage and further exacerbating the toxicities of these mitochondrial agents resulting in neurodegeneration. Rat dopaminergic neuronal cell culture and in vitro experiments using mouse brain mitochondria were employed to validate important features of the model.


CONCLUSIONS
Using a combination of experimental and in silico modeling approaches, we have demonstrated the interdependence of mitochondrial function with GSH metabolism in relation to neurodegeneration in PD.
Vali
S
S
Cell Works Group Inc., AECS Layout, Marathahalli, Bangalore 560037, India.
Mythri
R B
RB
Jagatha
B
B
Padiadpu
J
J
Ramanujan
K S
KS
Andersen
J K
JK
Gorin
F
F
Bharath
M M S
MM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D014450:Electron Transport Complex III / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005981:Glutathione Synthase / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008959:Models, Neurological; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017711:Nonlinear Dynamics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D012402:Rotenone; D009243:NAD; D000255:Adenosine Triphosphate; D005981:Glutathione Synthase; D014450:Electron Transport Complex III; D005978:Glutathione