An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration

There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease and amyotrophic lateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death in numerous model systems. Although protective nuclear responses such as antioxidant enzymes and bcl-2 may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ameliorating these diseases. (C) 1999 Elsevier Science B.V. All rights reserved.