Journal of Bioenergetics and Biomembranes

, Volume 36, Issue 4, pp 347–352

Protection Against Ischemic Brain Injury by Inhibition of Mitochondrial Oxidative Stress

  • Gary Fiskum
  • Robert E. Rosenthal
  • Viktoria Vereczki
  • Erica Martin
  • Gloria E. Hoffman
  • Christos Chinopoulos
  • Alicia Kowaltowski
Article

DOI: 10.1023/B:JOBB.0000041766.71376.81

Cite this article as:
Fiskum, G., Rosenthal, R.E., Vereczki, V. et al. J Bioenerg Biomembr (2004) 36: 347. doi:10.1023/B:JOBB.0000041766.71376.81

Abstract

Mitochondria are both targets and sources of oxidative stress. This dual relationship is particularly evident in experimental paradigms modeling ischemic brain injury. One mitochondrial metabolic enzyme that is particularly sensitive to oxidative inactivation is pyruvate dehydrogenase. This reaction is extremely important in the adult CNS that relies very heavily on carbohydrate metabolism, as it represents the sole bridge between anaerobic and aerobic metabolism. Oxidative injury to this enzyme and to other metabolic enzymes proximal to the electron transport chain may be responsible for the oxidized shift in cellular redox state that is observed during approximately the first hour of cerebral reperfusion. In addition to impairing cerebral energy metabolism, oxidative stress is a potent activator of apoptosis. The mechanisms responsible for this activation are poorly understood but likely involve the expression of p53 and possibly direct effects of reactive oxygen species on mitochondrial membrane proteins and lipids. Mitochondria also normally generate reactive oxygen species and contribute significantly to the elevated net production of these destructive agents during reperfusion. Approaches to inhibiting pathologic mitochondrial generation of reactive oxygen species include mild uncoupling, pharmacologic inhibition of the membrane permeability transition, and simply lowering the concentration of inspired oxygen. Antideath mitochondrial proteins of the Bcl-2 family also confer cellular resistance to oxidative stress, paradoxically through stimulation of mitochondrial free radical generation and secondary upregulation of antioxidant gene expression.

Superoxide nitric oxide peroxynitrite pyruvate dehydrogenase calcium apoptosis 

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Gary Fiskum
    • 1
    • 2
  • Robert E. Rosenthal
    • 1
    • 2
  • Viktoria Vereczki
    • 1
  • Erica Martin
    • 1
    • 2
  • Gloria E. Hoffman
    • 2
    • 3
  • Christos Chinopoulos
    • 1
  • Alicia Kowaltowski
    • 4
  1. 1.Department of AnesthesiologyUniversity of Maryland School of MedicineBaltimoreMaryland 21201
  2. 2.Program in NeuroscienceUniversity of Maryland School of MedicineBaltimoreMaryland
  3. 3.Department of Anatomy and NeurobiologyUniversity of Maryland School of MedicineBaltimoreMaryland
  4. 4.Departamento de Bioquímica, Instituto de QuímicaUniversidade deSão Paulo, SPBrazil