title: Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response.
abstract: 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.
authors.affiliation: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester LE1 9HN, UK.
authors.forename: N
authors.initials: N
authors.lastname: Moisoi
authors.forename: K
authors.initials: K
authors.lastname: Klupsch
authors.forename: V
authors.initials: V
authors.lastname: Fedele
authors.forename: P
authors.initials: P
authors.lastname: East
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.forename: A
authors.initials: A
authors.lastname: Renton
authors.forename: H
authors.initials: H
authors.lastname: Plun-Favreau
authors.forename: R E
authors.initials: RE
authors.lastname: Edwards
authors.forename: P
authors.initials: P
authors.lastname: Teismann
authors.forename: M D
authors.initials: MD
authors.lastname: Esposti
authors.forename: A D
authors.initials: AD
authors.lastname: Morrison
authors.forename: N W
authors.initials: NW
authors.lastname: Wood
authors.forename: J
authors.initials: J
authors.lastname: Downward
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000975:Antioxidants; C497250:Ddit3 protein, mouse; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse