Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases.
Considerable evidence indicates that oxidative stress accompanies age-related neurodegenerative diseases. Specific mechanisms by which oxidative stress leads to neurodegeneration are unknown. Two targets of oxidative stress that are known to change in neurodegenerative diseases are the mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (KGDHC) and endoplasmic reticulum calcium stores. KGDHC activities are diminished in all common neurodegenerative diseases and the changes are particularly well documented in Alzheimer's disease (AD). A second change that occurs in cells from AD patients is an exaggerated endoplasmic reticulum calcium store [i.e., bombesin-releasable calcium stores (BRCS)]. H(2)O(2), a general oxidant, changes both variables in the same direction as occurs in disease. Other oxidants selectively alter these variables. Various antioxidants were used to help define the critical oxidant species that modifies these responses. All of the antioxidants diminish the oxidant-induced carboxy-dichlorofluorescein (cDCF) detectable reactive oxygen species (ROS), but have diverse actions on these cellular processes. For example, alpha-keto-beta-methyl-n-valeric acid (KMV) diminishes the H(2)O(2) effects on BRCS, while trolox and DMSO exaggerate the response. Acute trolox treatment does not alter H(2)O(2)-induced changes in KGDHC, whereas chronic treatment with trolox increases KGDHC almost threefold. The results suggest that KGDHC and BRCS provide targets by which oxidative stress may induce neurodegeneration and a useful tool for selecting antioxidants for reversing age-related neurodegeneration.
Gibson
Gary E
GE
Burke Medical Research Institute, Weill Medical College of Cornell University, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
Huang
Hsueh-Meei
HM
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D002463:Cell Membrane Permeability; D019069:Cell Respiration / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000975:Antioxidants; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D007655:Ketoglutarate Dehydrogenase Complex; D002118:Calcium