title: Novel mitochondrial targets for neuroprotection.
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.
authors.affiliation: Department of Neurology, Cerebral Vascular Disease Research Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perez-Pinzon
authors.forename: R Anne
authors.initials: RA
authors.lastname: Stetler
authors.forename: Gary
authors.initials: G
authors.lastname: Fiskum
mesh_terms: D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents