Production of Reactive Oxygen Species in Brain Mitochondria: Contribution by Electron Transport Chain and Non–Electron Transport Chain Sources
Autor: | Vera Adam-Vizi |
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Rok vydání: | 2005 |
Předmět: |
N-Methylaspartate
Physiology Clinical Biochemistry Respiratory chain Biology Mitochondrion medicine.disease_cause Models Biological Biochemistry Gene Expression Regulation Enzymologic Membrane Potentials Electron Transport chemistry.chemical_compound Superoxides medicine Animals Humans Ketoglutarate Dehydrogenase Complex Molecular Biology General Environmental Science chemistry.chemical_classification Reactive oxygen species Superoxide Dismutase Superoxide Brain Hydrogen Peroxide Cell Biology Electron transport chain Mitochondria Rats Oxidative Stress Cytosol Electron Transport Chain Complex Proteins chemistry Coenzyme Q – cytochrome c reductase Biophysics General Earth and Planetary Sciences Reactive Oxygen Species Oxidative stress |
Zdroj: | Antioxidants & Redox Signaling. 7:1140-1149 |
ISSN: | 1557-7716 1523-0864 |
Popis: | Overwhelming evidence has accumulated indicating that oxidative stress is a crucial factor in the pathogenesis of neurodegenerative diseases. The major site of production of superoxide, the primary reactive oxygen species (ROS), is considered to be the respiratory chain in the mitochondria, but the exact mechanism and the precise location of the physiologically relevant ROS generation within the respiratory chain have not been disclosed as yet. Studies performed with isolated mitochondria have located ROS generation on complex I and complex III, respectively, depending on the substrates or inhibitors used to fuel or inhibit respiration. A more "physiological" approach is to address ROS generation of in situ mitochondria, which are present in their normal cytosolic environment. Hydrogen peroxide formation in mitochondria in situ in isolated nerve terminals is enhanced when complex I, complex III, or complex IV is inhibited. However, to induce a significant increase in ROS production, complex III and complex IV have to be inhibited by70%, which raises doubts as to the physiological importance of ROS generation by these complexes. In contrast, complex I inhibition to a small degree is sufficient to enhance ROS generation, indicating that inhibition of complex I by approximately 25-30% observed in postmortem samples of substantia nigra from patients suffering from Parkinson's disease could be important in inducing oxidative stress. Recently, it has been described that a key Krebs cycle enzyme, alpha-ketoglutarate dehydrogenase (alpha-KGDH), is also able to produce ROS. ROS formation by alpha-KGDH is regulated by the NADH/NAD+ ratio, suggesting that this enzyme could substantially contribute to generation of oxidative stress due to inhibition of complex I. As alpha-KGDH is not only a generator but also a target of ROS, it is proposed that alpha-KGDH is a key factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals. |
Databáze: | OpenAIRE |
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