Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 52, Pages 19126-19131Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508215102
Keywords
mitochondria; neurodegeneration; Parkinson's disease
Categories
Funding
- NIA NIH HHS [AG21617, R01 AG021617] Funding Source: Medline
- NINDS NIH HHS [NS38370, P50 NS038370, NS11766, R01 NS038586, NS42269, P01 NS011766, NS38586, R01 NS042269] Funding Source: Medline
- Telethon [GGP02323] Funding Source: Medline
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Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.
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