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 neurodegenerati ve diseases including Alzheimer's and Parkinson's disease and amyotrophic l ateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquire d, lead to impaired electron transport chain (ETC) functioning. Impaired el ectron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequen ces of ETC dysfunction lead to further mitochondrial damage including oxida tion of mitochondrial DNA, proteins, and lipids, and opening of the mitocho ndrial permeability transition pore, an event linked to cell death in numer ous model systems. Although protective nuclear responses such as antioxidan t enzymes and bcl-2 may be induced to combat these pathological changes, su ch a vicious cycle of increasing oxidative damage may insidiously damage ne urons over a period of years, eventually leading to neuronal cell death. Th is hypothesis, a synthesis of the mitochondrial mutations and oxidative str ess hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ame liorating these diseases. (C) 1999 Elsevier Science B.V. All rights reserve d.