Premium
An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH‐SY5Y cells
Author(s) -
ShamotoNagai Masayo,
Maruyama Wakako,
Kato Yoji,
Isobe Kenichi,
Tanaka Masashi,
Naoi Makoto,
Osawa Toshihiko
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10777
Subject(s) - rotenone , proteasome , mitochondrion , sh sy5y , oxidative phosphorylation , oxidative stress , microbiology and biotechnology , chemistry , reactive oxygen species , programmed cell death , biochemistry , protein subunit , biology , apoptosis , cell culture , neuroblastoma , gene , genetics
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 β 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 β 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. © 2003 Wiley‐Liss, Inc.