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

Celine Perier, Kim Tieu, Christelle Guégan, Casper Caspersen, Vernice Jackson-Lewis, Valerio Carelli, Andréa Martinuzzi, Michio Hirano, Serge Przedborski, Miquel Vila

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Pages (from-to)19126-19131
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
Publication statusPublished - Dec 27 2005


  • Mitochondria
  • Neurodegeneration
  • Parkinson's disease

ASJC Scopus subject areas

  • Genetics
  • General


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