Mitochondria: A therapeutic target in neurodegeneration

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 10/2009; 1802(1):212-20. DOI: 10.1016/j.bbadis.2009.10.007
Source: PubMed

ABSTRACT Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.

Download full-text


Available from: George Perry, Jun 22, 2015
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative and nitrosative stress (ONS) contributes to the pathogenesis of most brain maladies, and the magnitude of ONS is related to the ability of cellular antioxidants to neutralize the accumulating reactive oxygen and nitrogen species (ROS/RNS). While the major ROS/RNS scavengers and regenerators of bio-oxidized molecules: superoxide dysmutases (SODs), glutathione (GSH), thioredoxin (Trx) and peroxiredoxin (Prx) are distributed in all cellular compartments. This review specifically focuses on the role of the systems operating in mitochondria. There is a growing consensus that the mitochondrial SOD isoform - SOD2 and GSH are critical for the cellular antioxidant defense. Variable changes of the expression or activities of one or more of the mitochondrial antioxidant systems have been documented in the brains derived from human patients and/or in animal models of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebral ischemia, toxic brain cell damage associated with overexposure to mercury or excitotoxins, or hepatic encephalopathy. In many cases, ambiguity of the responses of the different antioxidant systems in one and the same disease need to be more conclusively evaluated before the balance of the changes in viewed as beneficial or detrimental. Modulation of the mitochondrial antioxidant systems may in the future become a target of antioxidant therapy. Copyright © 2014. Published by Elsevier Ltd.
    Neurochemistry International 01/2015; DOI:10.1016/j.neuint.2014.12.012 · 2.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The cell is known to be the most basic unit of life. However, this basic unit of life is dependent on the proper function of many intracellular organelles to thrive. One specific organelle that has vast implications on the overall health of the cell and cellular viability is the mitochondrion. These cellular power plants generate the energy currency necessary for cells to maintain homeostasis and function properly. Additionally, when mitochondria become dysfunctional, they can orchestrate the cell to undergo cell-death. Therefore, it is important to understand what insults can lead to mitochondrial dysfunction in order to promote cell health and increase cellular viability. After years of research, is has become increasingly accepted that age has a negative effect on mitochondrial bioenergetics. In support of this, we have found decreased mitochondrial bioenergetics with increased age in Sprague-Dawley rats. Within this same study we found a 200 to 600 % increase in ROS production in old rats compared to young rats. Additionally, the extent of mitochondrial dysfunction and ROS production seems to be spatially defined affecting the spinal cord to a greater extent than certain regions of the brain. These tissue specific differences in mitochondrial function may be the reason why certain regions of the Central Nervous System, CNS, are disproportionately affected by aging and may play a pivotal role in specific age-related neurodegenerative diseases like Amyotrophic Lateral Sclerosis, ALS.
    Journal of Bioenergetics 12/2014; 47(1-2). DOI:10.1007/s10863-014-9593-5 · 2.71 Impact Factor