ABSTRACT
In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produces reactive oxygen and nitrogen species, which may account for neuronal cell death in neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. In these disorders, inclusion body composed of oxidation-modified proteins and lipids is detected specifically for distinct diseases, such as the Lewy body for Parkinson’s disease. The relationship between mitochondrial dysfunction, increased oxidative stress, accumulation of oxidation-modified protein, and final cell death of definite neurons in the brain remains to be clarified. In this paper, we review our recent results on interaction among these factors in neurons, using a cellular model of apoptosis induced by peroxynitrite-generating N-Morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone in human dopaminergic SH-SY5Y cells. In control cells, 3-nitrotyrosine-containing protein produced by peroxynitrite was detected, suggesting that neurons exist in a state of constant oxidative stress. N-Morpholino sydnonimine induced apoptosis and reduction in ATP level, which is, increased further by an inhibitor of proteasome, carbobenzoxy-lisoleucyl-g-t-butyl-glutamyl-l-alanyl-l-leucinal (PSI). The subunits of mitochondrial complex I were found to contain 3-nitrotyrosine, suggesting that peroxynitrite prefers these enzymes. In addition, rotenone induced mitochondrial dysfunction, and accumulation and aggregation of protein modified with acrolein, an aldehyde product of lipid peroxidation. Rotenone treatment reduced the enzymatic activity of the proteasome system, a major organelle in the degradation of oxidation-modified protein, and it was due to the oxidative modification of 20S b subunit of the proteasome. These results are discussed in relation to the interaction between mitochondrial dysfunction, oxidative stress, and proteasome inactivation, resulting in neuronal cell death in neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease.
