The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?

Stroke and neurodegenerative disease exert an increasing large toll on human health at the levels both of the individual and of society. As an example of each, in the United States, stroke is the major single cause of overall morbidity and mortality, and the financial costs of Alzheimer's disease alone dwarfs the entire federal medical research budget. It has been long recognized that mitochondrial energy production is essential for the second to second functions of the central nervous system (CNS), and that severe mitochondrial impairment is incompatible with normal cerebral function. The last decade, however, has brought a growing understanding that mitochondria play an even greater role than previously Suspected. Increased understanding of the role of mitochondria in antioxidant defense and calcium homeostasis further solidified the importance of mitochondria in CNS function - just as increased understanding of mitochondrial roles in calcium-mediated toxicity and production of reactive species further exemplified the Janus role of mitochondria - as mediators of CNS dysfunction. Perhaps most unexpected, however, was the evidence that mitochondria serve as the dominant integrators, checkpoints, and amplifiers of the cell death signals in the CNS. The mechanism of propagation of cell death cascades by mitochondria remains controversial. In this review, we focus Oil the evidence that supports the involvement of ail event termed the mitochondrial permeability transition that (i) occurs (patho)physiologically; (ii) occurs in the CNS, and; (iii) is a potential target for pharmaceutical intervention against CNS dysfunction, injury, and cell loss resulting from stroke, trauma, and neurodegenerative disease. (C) 2004 Elsevier Inc. All rights reserved.