Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication.
Chronic infusion of rotenone (Rot) to Lewis rats reproduces many features of Parkinson disease. Rot (3 mg/kg/day) was infused subcutaneously to male Lewis rats for 6 days using Alzet minipumps. Control rats received the vehicle only. Presence of 0.1% bovine serum albumin during the isolation procedure completely removed rotenone bound to the mitochondria. Therefore all functional changes observed were aftereffects of rotenone toxicity in vivo. In Rot rat brain mitochondria (Rot-RBM) there was a 30-40% inhibition of respiration in State 3 and State 3U with Complex I (Co-I) substrates and succinate. Rot did not affect the State 4Deltapsi of RBM and rat liver mitochondria (RLM). However, Rot-RBM required two times less Ca2+ to initiate permeability transition (mPT). There was a 2-fold increase in O*2- or H2O2 generation in Rot-RBM oxidizing glutamate. Rot infusion affected RLM little. Our results show that in RBM, the major site of reactive oxygen species generation with glutamate or succinate is Co-I. We also found that Co-II generates substantial amounts of reactive oxygen species that increased 2-fold in the Rot-RBM. Our data suggest that the primary mechanism of the Rot toxic effect on RBM consists in a significant increase of O*2- generation that causes damage to Co-I and Co-II, presumably at the level of 4Fe-4S clusters. Decreased respiratory activity diminishes resistance of RBM to Ca2+ and thus increases probability of mPT and apoptotic cell death. We suggest that the damage to Co-I and Co-II shifts O*2- generation from the CoQ10 sites to more proximal sites, such as flavines, and makes it independent of the RBM functional state.
Panov
Alexander
A
Carolinas Neuromuscular/ALS-MDA Center, Carolinas Medical Center, Charlotte, North Carolina 28203, USA. alexander.panov@carolinashealthcare.org
Dikalov
Sergey
S
Shalbuyeva
Natalia
N
Taylor
Georgia
G
Sherer
Todd
T
Greenamyre
J Timothy
JT
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010300:Parkinson Disease / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000633:toxicity*
D012402:Rotenone