Production of reactive oxygen species in brain mitochondria: Contribution by electron transport chain and non-electron transport chain sources

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Abstract

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 by >70%, 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 ∼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, α-ketoglutarate dehydrogenase (α-KGDH), is also able to produce ROS. ROS formation by α-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 α-KGDH is not only a generator but also a target of ROS, it is proposed that α-KGDH is a key factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals.

Original languageEnglish
Pages (from-to)1140-1149
Number of pages10
JournalAntioxidants and Redox Signaling
Volume7
Issue number9-10
DOIs
Publication statusPublished - Sep 2005

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Mitochondria
Electron Transport
Reactive Oxygen Species
Brain
Oxidative stress
Electron Transport Complex III
Oxidative Stress
NAD
Neurodegenerative diseases
Citric Acid Cycle
Substantia Nigra
Enzymes
Superoxides
Neurodegenerative Diseases
Hydrogen Peroxide
Parkinson Disease
Oxidoreductases
Respiration

ASJC Scopus subject areas

  • Biochemistry

Cite this

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abstract = "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 by >70{\%}, 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 ∼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, α-ketoglutarate dehydrogenase (α-KGDH), is also able to produce ROS. ROS formation by α-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 α-KGDH is not only a generator but also a target of ROS, it is proposed that α-KGDH is a key factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals.",
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