Oxidative stress in mitochondria: decision to survival and death of neurons in neurodegenerative disorders.
In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson's and Alzheimer's disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone, in human dopaminergic SH-SY5Y cells. In control cells, peroxynitrite nitrated proteins, especially the subunits of mitochondrial complex I, as 3-nitrotyrosine, suggesting that neurons are exposed to constant oxidative stress even under physiological conditions. SIN-1 and an inhibitor of proteasome, carbobenzoxy-L-isoleucyl-gamma-t-butyl-L-alanyl-L-leucinal (PSI), increased markedly the levels of nitrated proteins with concomitant induction of apoptosis in the cells. Rotenone induced mitochondrial dysfunction and accumulation and aggregation of proteins modified with acrolein, an aldehyde product of lipid peroxidation in the cells. At the same time, the activity of the 20S beta-subunit of proteasome was reduced significantly, which degrades oxidative-modified protein. The mechanism was proved to be the result of the modification of the 20S beta-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S beta-subunit.
Naoi
Makoto
M
Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan. mnaoi@giib.or.jp
Maruyama
Wakako
W
Shamoto-Nagai
Masayo
M
Yi
Hong
H
Akao
Yukihiro
Y
Tanaka
Masashi
M
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*