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Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.


ABSTRACT: 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.

SUBMITTER: Perier C 

PROVIDER: S-EPMC1323177 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.

Perier Celine C   Tieu Kim K   Guégan Christelle C   Caspersen Casper C   Jackson-Lewis Vernice V   Carelli Valerio V   Martinuzzi Andrea A   Hirano Michio M   Przedborski Serge S   Vila Miquel M  

Proceedings of the National Academy of Sciences of the United States of America 20051219 52


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 oxi  ...[more]

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