Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

N Moisoi, K Klupsch, V Fedele, P East, S Sharma, A Renton, H Plun-Favreau, R E Edwards, P Teismann, M D Esposti, A D Morrison, N W Wood, J Downward, L M Martins

Research output: Contribution to journalArticlepeer-review

150 Citations (Scopus)


Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.
Original languageEnglish
Pages (from-to)449-464
Number of pages16
JournalCell Death and Differentiation
Issue number3
Early online date21 Nov 2008
Publication statusPublished - 2009


  • animals
  • antioxidants
  • brain
  • cell respiration
  • corpus striatum
  • humans
  • mice
  • mice, knockout
  • mitochondria
  • mitochondrial proteins
  • molecular sequence data
  • neurons
  • oxidative stress
  • Parkinson disease
  • reactive oxygen species
  • serine endopeptidases
  • tissue distribution
  • transcription factor CHOP
  • transcription, genetic
  • CHOP
  • HtRA2
  • integrated stress response
  • PARK13
  • parkinsonian syndrome


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