Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease

Proc Natl Acad Sci U S A. 2007 May 8;104(19):8161-6. doi: 10.1073/pnas.0609874104. Epub 2007 May 2.


Dysfunction of mitochondrial complex I is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). In rodents, inhibition of complex I leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc), as seen in PD, through activation of mitochondria-dependent apoptotic molecular pathways. In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro-cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol. Activation of Bax after complex I inhibition relies on its transcriptional induction and translocation to the mitochondria. How complex I deficiency leads to Bax activation is currently unknown. Using gene-targeted mice, we show that the tumor suppressor p53 mediates Bax transcriptional induction after PD-related complex I blockade in vivo, but it does not participate in Bax mitochondrial translocation in this model, either by a transcription-independent mechanism or through the induction of BH3-only proteins Puma or Noxa. Instead, Bax mitochondrial translocation in this model relies mainly on the JNK-dependent activation of the BH3-only protein Bim. Targeting either Bax transcriptional induction or Bax mitochondrial translocation results in a marked attenuation of SNpc dopaminergic cell death caused by complex I inhibition. These results provide further insight into the pathogenesis of PD neurodegeneration and identify molecular targets of potential therapeutic significance for this disabling neurological illness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • DNA Damage
  • Electron Transport Complex I / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / physiology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / physiology*
  • Neurodegenerative Diseases / etiology*
  • Parkinsonian Disorders / pathology*
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Substantia Nigra / pathology*
  • Tumor Suppressor Protein p53 / physiology
  • bcl-2-Associated X Protein / metabolism


  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • JNK Mitogen-Activated Protein Kinases
  • Electron Transport Complex I