Mitochondrial dysfunction in neurodegenerative diseases.
A potential pivotal role for mitochondrial dysfunction in neurodegenerative diseases is gaining increasing acceptance. Mitochondrial dysfunction leads to a number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Neurodegenerative diseases of widely disparate genetic etiologies may share mitochondrial dysfunction as a final common pathway. Recent studies using cybrid cell lines suggest that sporadic Alzheimer's disease is associated with a deficiency of cytochrome oxidase. Friedreich's ataxia is caused by an expanded GAA repeat resulting in dysfunction of frataxin, a nuclear encoded mitochondrial protein involved in mitochondrial iron transport. This results in increased mitochondrial iron and oxidative damage. Familial amyotrophic lateral sclerosis is associated with point mutations in superoxide dismutase, which may lead to increased generation of free radicals and thereby contribute to mitochondrial dysfunction. Huntington's disease (HD) is caused by an expanded CAG repeat in an unknown protein termed huntingtin. The means by which this leads to energy impairment is unclear, however studies in both HD patients and a transgenic mouse model show evidence of bioenergetic defects. Mitochondrial dysfunction leads to oxidative damage which is well documented in several neurodegenerative diseases. Therapeutic approaches include methods to buffer intracellular ATP and to scavenge free radicals.
Beal
M F
MF
Neurology Service/WRN 408, Massachusetts General Hospital and Harvard Medical School, 32 Fruit Street, Boston, MA 02114, USA. beal@helix.harvard.mgh.edu
D000544:Alzheimer Disease / Q000209:etiology; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics*; D005621:Friedreich Ataxia / Q000209:etiology; D006801:Humans; D006816:Huntington Disease / Q000209:etiology; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics* / Q000628:therapy; D018384:Oxidative Stress / Q000235:genetics