6.5 Mitochondrial Mechanisms of Oxidative Stress and Apoptosis
While it has long been appreciated that mitochondrial dysfunction can lead to metabolic failure and necrotic cell death, more recent work has highlighted the central role that mitochondria play in oxidative stress and apoptosis, including their involvemen
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Mitochondrial Mechanisms of Oxidative Stress and Apoptosis
L. Soane . N. Solenski . G. Fiskum
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
2 2.1 2.2 2.3 2.4 2.5 2.6 2.7
Oxidative Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 Contribution of Oxidative Stress to Neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 Mitochondria as Sources of Reactive Oxygen Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706 Mitochondrial Antioxidant Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709 Formation of Nitric Oxide in the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710 NMDA Receptor and nNOS Activation Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711 Mitochondrial Formation of NO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711 Mitochondria as Targets of Reactive Oxygen and Nitrogen Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
3 3.1 3.2 3.3 3.4
Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 Intrinsic and Extrinsic Apoptotic Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715 Proapoptotic Bcl‐2 Family Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717 Antiapoptotic Bcl‐2 Family Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720 Antiapoptotic Drugs and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
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Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
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Springer-Verlag Berlin Heidelberg 2007
704
6.5
Mitochondrial mechanisms of oxidative stress and apoptosis
Abstract: While it has long been appreciated that mitochondrial dysfunction can lead to metabolic failure and necrotic cell death, more recent work has highlighted the central role that mitochondria play in oxidative stress and apoptosis, including their involvement in neurodegeneration. Factors that promote mitochondrial production
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