Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes

Gary Fiskum, Camelia A. Danilov, Zara Mehrabian, Linda L. Bambrick, Tibor Kristian, Mary C. McKenna, Irene Hopkins, E. M. Richards, Robert E. Rosenthal

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

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 O2 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 O2 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.

Original languageEnglish (US)
Title of host publicationMitochondria and Oxidative Stress in Neurodegenerative Disorders
PublisherBlackwell Publishing Inc.
Pages129-138
Number of pages10
ISBN (Print)9781573317139
DOIs
StatePublished - Dec 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1147
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Nicotinamide adenine dinucleotide
  • Pyruvate dehydrogenase
  • Respiration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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  • Cite this

    Fiskum, G., Danilov, C. A., Mehrabian, Z., Bambrick, L. L., Kristian, T., McKenna, M. C., Hopkins, I., Richards, E. M., & Rosenthal, R. E. (2008). Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes. In Mitochondria and Oxidative Stress in Neurodegenerative Disorders (pp. 129-138). (Annals of the New York Academy of Sciences; Vol. 1147). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1427.026