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.
| Original language | English |
|---|---|
| Pages (from-to) | 19126-19131 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 102 |
| Issue number | 52 |
| DOIs | |
| Publication status | Published - Dec 27 2005 |
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Keywords
- Mitochondria
- Neurodegeneration
- Parkinson's disease
ASJC Scopus subject areas
- Genetics
- General
Cite this
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. / Perier, Celine; Tieu, Kim; Guégan, Christelle; Caspersen, Casper; Jackson-Lewis, Vernice; Carelli, Valerio; Martinuzzi, Andréa; Hirano, Michio; Przedborski, Serge; Vila, Miquel.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 52, 27.12.2005, p. 19126-19131.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage
AU - Perier, Celine
AU - Tieu, Kim
AU - Guégan, Christelle
AU - Caspersen, Casper
AU - Jackson-Lewis, Vernice
AU - Carelli, Valerio
AU - Martinuzzi, Andréa
AU - Hirano, Michio
AU - Przedborski, Serge
AU - Vila, Miquel
PY - 2005/12/27
Y1 - 2005/12/27
N2 - 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.
AB - 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.
KW - Mitochondria
KW - Neurodegeneration
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=30044442094&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30044442094&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508215102
DO - 10.1073/pnas.0508215102
M3 - Article
C2 - 16365298
AN - SCOPUS:30044442094
VL - 102
SP - 19126
EP - 19131
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 52
ER -