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Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson's disease
Author(s) -
Höglinger Günter U.,
Carrard Géraldine,
Michel Patrick P.,
Medja Fadia,
Lombès Anne,
Ruberg Merle,
Friguet Bertrand,
Hirsch Etienne C.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01952.x
Subject(s) - rotenone , proteasome , chemistry , adenosine triphosphate , pharmacology , oxidative stress , biochemistry , mitochondrion , biology
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.