Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease.
Two biochemical deficits have been described in the substantia nigra in Parkinson's disease, decreased activity of mitochondrial complex I and reduced proteasomal activity. We analysed interactions between these deficits in primary mesencephalic cultures. Proteasome inhibitors (epoxomicin, MG132) exacerbated the toxicity of complex I inhibitors [rotenone, 1-methyl-4-phenylpyridinium (MPP+)] and of the toxic dopamine analogue 6-hydroxydopamine, but not of inhibitors of mitochondrial complex II-V or excitotoxins [N-methyl-d-aspartate (NMDA), kainate]. Rotenone and MPP+ increased free radicals and reduced proteasomal activity via adenosine triphosphate (ATP) depletion. 6-hydroxydopamine also increased free radicals, but did not affect ATP levels and increased proteasomal activity, presumably in response to oxidative damage. Proteasome inhibition potentiated the toxicity of rotenone, MPP+ and 6-hydroxydopamine at concentrations at which they increased free radical levels >/= 40% above baseline, exceeding the cellular capacity to detoxify oxidized proteins reduced by proteasome inhibition, and also exacerbated ATP depletion caused by complex I inhibition. Consistently, both free radical scavenging and stimulation of ATP production by glucose supplementation protected against the synergistic toxicity. In summary, proteasome inhibition increases neuronal vulnerability to normally subtoxic levels of free radicals and amplifies energy depletion following complex I inhibition.
Höglinger
Günter U
GU
INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. gunter@ccr.jussieu.fr
Carrard
Géraldine
G
Michel
Patrick P
PP
Medja
Fadia
F
Lombès
Anne
A
Ruberg
Merle
M
Friguet
Bertrand
B
Hirsch
Etienne C
EC
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium