Novel mitochondrial targets for neuroprotection

Miguel A. Perez-Pinzon, R. Anne Stetler, Gary Fiskum

Research output: Contribution to journalReview article

107 Scopus citations

Abstract

Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity- associated mitochondrial Ca 2 overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O 2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca 2-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.

Original languageEnglish (US)
Pages (from-to)1362-1376
Number of pages15
JournalJournal of Cerebral Blood Flow and Metabolism
Volume32
Issue number7
DOIs
StatePublished - Jul 1 2012

Keywords

  • Biogenesis
  • mitophagy
  • Nrf2
  • oxidative stress
  • peroxisome proliferator- activated receptor-gamma coactivator 1a
  • protein kinase C

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

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