Mitochondrial oxidative stress and nuclear responses in sporadic neurodegenerative diseases.

摘要

There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease. 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. I have provided evidence that damaged mitochondria signal the nucleus to upregulate both pro-(via mitochondrial transition pore activation, cytochrome c release, and caspase activation) and antiapoptotic (such as NF-κB and the antioxidant enzymes) forces. These results advance our understanding of the role of mitochondria in cell death in neurodegenerative diseases, and clearly point out many potential therapeutic targets for preventing or ameliorating these diseases.