Neuroprotection through stimulation of mitochondrial antioxidant protein expression

  • Greco T
  • Fiskum G
  • 21

    Readers

    Mendeley users who have this article in their library.
  • 25

    Citations

    Citations of this article.

Abstract

Oxidative stress and loss of cellular Ca2+ homeostasis are closely linked and are common denominators in the pathophysiology of many neurodegenerative diseases and acute disorders of the nervous system. Mitochondria are major targets of oxidative stress and abnormal intracellular Ca2+, as both can cause bioenergetic failure through synergistic activation of the mitochondrial inner membrane permeability transition pore. Opening of this molecularly ill-defined pore causes both collapse of the membrane potential, which drives oxidative phosphorylation, and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defense against oxidative stress. Expression of genes coding for many antioxidant defense proteins is regulated by the Nrf2 transcriptional activating factor. Translocation of this protein from the cytosol to the nucleus is stimulated by oxidative stress and by specific agents that either react with cysteine sulfhydryl groups present on the protein KEAP1, that normally binds and restricts Nrf2 translocation, or that stimulate serine phosphorylation of Nrf2. Recent evidence indicates that mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway can increase resistance to redox-regulated opening of the permeability transition pore. Pharmacologic stimulation of the Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury.

Author-supplied keywords

  • Antioxidant
  • Nrf2
  • bioenergetics
  • calcium
  • cerebral ischemia
  • neurodegeneration
  • oxidative stress
  • permeability transition pore

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • Tiffany Greco

  • Gary Fiskum

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free