Oxidative stress in mitochondria |
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Authors: | Makoto Naoi Wakako Maruyama Masayo Shamoto-Nagai Hong Yi Yukihiro Akao Masashi Tanaka |
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Institution: | (1) Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan;(2) Department of Geriatrics, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan |
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Abstract: | 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-γ-t-butyl-l-analyl-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 β-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 β-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S β-subunit.
Increased oxidative stress caused by SIN-1 treatment induced a decline in the mitochondrial membrane potential, ΔΨm, and activated
mitochondrial apoptotic signaling and induced cell death in SH-SY5Y cells. As another pathway, p38 mitogen-activated protein
(MAP) kinase and exracellular signal-regulated kinase (ERK) mediated apoptosis induced by SIN-1. On the other hand, a series
of neuroprotective propargylamine derivatives, including rasagiline N-propargyl-1(R)aminoindan]and (−)deprenyl, intervened in the activation of apoptotic cascade by reactive oxygen species-reactive nitrogen
species in mitochondria through stabilization of the membrane potential, ΔΨm. In addition, rasagiline induced antiapoptotic
Bcl-2 and glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells, which was mediated by the ERK-nuclear factor
(NF)-κB pathway. These results are discussed in relation to the interaction of oxidative stress and mitochondria in the regulation
of neuronal death and survival in neurodegenerative diseases. |
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