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Postischemic Oxidative Stress Promotes Mitochondrial Metabolic Failure in Neurons and Astrocytes
Author(s) -
Fiskum Gary,
Danilov Camelia A.,
Mehrabian Zara,
Bambrick Linda L.,
Kristian Tibor,
McKenna Mary C.,
Hopkins Irene,
Richards E. M.,
Rosenthal Robert E.
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1427.026
Subject(s) - oxidative stress , mitochondrion , mitochondrial permeability transition pore , oxidative phosphorylation , nad+ kinase , biology , bioenergetics , microbiology and biotechnology , neuroscience , programmed cell death , biochemistry , apoptosis , enzyme
Oxidative stress and mitochondrial dysfunction have been closely associated in many subcellular, cellular, animal, and human studies of both acute brain injury and neurodegenerative diseases. Our animal models of brain injury caused by cardiac arrest illustrate this relationship and demonstrate that both oxidative molecular modifications and mitochondrial metabolic impairment are exacerbated by reoxygenation of the brain using 100% ventilatory O 2 compared to lower levels that maintain normoxemia. Numerous molecular mechanisms may be responsible for mitochondrial dysfunction caused by oxidative stress, including oxidation and inactivation of mitochondrial proteins, promotion of the mitochondrial membrane permeability transition, and consumption of metabolic cofactors and intermediates, for example, NAD(H). Moreover, the relative contribution of these mechanisms to cell injury and death is likely different among different types of brain cells, for example, neurons and astrocytes. In order to better understand these oxidative stress mechanisms and their relevance to neurologic disorders, we have undertaken studies with primary cultures of astrocytes and neurons exposed to O 2 and glucose deprivation and reoxygenation and compared the results of these studies to those using a rat model of neonatal asphyxic brain injury. These results support the hypothesis that release and or consumption of mitochondrial NAD(H) is at least partially responsible for respiratory inhibition, particularly in neurons.