An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells.
In Parkinson's disease, characteristic pathological features are the cell death of nigrostriatal dopamine neurons and the formation of Lewy bodies composed of oxidized proteins. Mitochondrial dysfunction and aggregation of abnormal proteins have been proposed to cause the pathological changes. However, the relation between these two factors remains to be clarified. In this study, the effects of mitochondrial dysfunction on the oxidative modification and accumulation of proteins were analyzed using an inhibitor of mitochondrial complex I, rotenone, and antibodies against acrolein- and dityrosine-modified proteins. Under conditions inducing mainly apoptosis in neuroblastoma SH-SY5Y cells, rotenone markedly increased oxidized proteins, especially those modified with acrolein, even though the increase in intracellular reactive oxygen and nitrogen species was only transient and was not so marked. In addition, the activity of the proteasome system degrading oxidized proteins was reduced profoundly after treatment with rotenone. The 20S beta subunit of proteasome was modified with acrolein, to which other acrolein-modified proteins were found to bind, as shown by coprecipitation with the antibody against 20S beta subunit. These results suggest that mitochondrial dysfunction, especially decreased activity of complex I, may reduce proteasome activity through oxidative modification of proteasome itself and aggregation with other oxidized proteins. This mechanism might account for the accumulation of modified protein and, at least partially, for cell death of the dopamine neurons in Parkinson's disease.
Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi, Japan.
Masayo
M
Shamoto-Nagai
Wakako
W
Maruyama
Yoji
Y
Kato
Ken-ichi
K
Isobe
Masashi
M
Tanaka
Makoto
M
Naoi
Toshihiko
T
Osawa
D000171:Acrolein / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D012402:Rotenone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology*
D009097:Multienzyme Complexes; D014475:Uncoupling Agents; D012402:Rotenone; D000171:Acrolein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex