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@ARTICLE{Fitzgerald:139474,
      author       = {Fitzgerald, Julia and Zimprich, Alexander and Carvajal
                      Berrio, Daniel A and Schindler, Kevin M and Maurer, Brigitte
                      and Schulte, Claudia and Bus, Christine and Hauser,
                      Ann-Kathrin and Kübler, Manuela and Lewin, Rahel and
                      Bobbili, Dheeraj Reddy and Schwarz, Lisa M and
                      Vartholomaiou, Evangelia and Brockmann, Kathrin and Wüst,
                      Richard and Madlung, Johannes and Nordheim, Alfred and
                      Riess, Olaf and Martins, L Miguel and Glaab, Enrico and May,
                      Patrick and Schenke-Layland, Katja and Picard, Didier and
                      Sharma, Manu and Gasser, Thomas and Krüger, Rejko},
      title        = {{M}etformin reverses {TRAP}1 mutation-associated
                      alterations in mitochondrial function in {P}arkinson's
                      disease.},
      journal      = {Brain},
      volume       = {140},
      number       = {9},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-05796},
      pages        = {2444-2459},
      year         = {2017},
      abstract     = {The mitochondrial proteins TRAP1 and HTRA2 have previously
                      been shown to be phosphorylated in the presence of the
                      Parkinson's disease kinase PINK1 but the downstream
                      signalling is unknown. HTRA2 and PINK1 loss of function
                      causes parkinsonism in humans and animals. Here, we
                      identified TRAP1 as an interactor of HTRA2 using an unbiased
                      mass spectrometry approach. In our human cell models, TRAP1
                      overexpression is protective, rescuing HTRA2 and
                      PINK1-associated mitochondrial dysfunction and suggesting
                      that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2
                      regulates TRAP1 protein levels, but TRAP1 is not a direct
                      target of HTRA2 protease activity. Following genetic
                      screening of Parkinson's disease patients and healthy
                      controls, we also report the first TRAP1 mutation leading to
                      complete loss of functional protein in a patient with late
                      onset Parkinson's disease. Analysis of fibroblasts derived
                      from the patient reveal that oxygen consumption, ATP output
                      and reactive oxygen species are increased compared to
                      healthy individuals. This is coupled with an increased pool
                      of free NADH, increased mitochondrial biogenesis, triggering
                      of the mitochondrial unfolded protein response, loss of
                      mitochondrial membrane potential and sensitivity to
                      mitochondrial removal and apoptosis. These data highlight
                      the role of TRAP1 in the regulation of energy metabolism and
                      mitochondrial quality control. Interestingly, the diabetes
                      drug metformin reverses mutation-associated alterations on
                      energy metabolism, mitochondrial biogenesis and restores
                      mitochondrial membrane potential. In summary, our data show
                      that TRAP1 acts downstream of PINK1 and HTRA2 for
                      mitochondrial fine tuning, whereas TRAP1 loss of function
                      leads to reduced control of energy metabolism, ultimately
                      impacting mitochondrial membrane potential. These findings
                      offer new insight into mitochondrial pathologies in
                      Parkinson's disease and provide new prospects for targeted
                      therapies.},
      keywords     = {Adenosine Triphosphate: metabolism / Apoptosis: drug
                      effects / Case-Control Studies / Cells, Cultured /
                      Fibroblasts: metabolism / HSP90 Heat-Shock Proteins:
                      biosynthesis / HSP90 Heat-Shock Proteins: genetics /
                      High-Temperature Requirement A Serine Peptidase 2 / Humans /
                      Membrane Potential, Mitochondrial: physiology / Metformin:
                      therapeutic use / Mitochondria: drug effects / Mitochondria:
                      genetics / Mitochondria: metabolism / Mitochondrial
                      Proteins: metabolism / Mutation / NAD: metabolism /
                      Organelle Biogenesis / Oxygen Consumption / Parkinson
                      Disease: drug therapy / Parkinson Disease: genetics /
                      Parkinson Disease: metabolism / Protein Kinases: metabolism
                      / Reactive Oxygen Species: metabolism / Serine
                      Endopeptidases: metabolism / HSP90 Heat-Shock Proteins (NLM
                      Chemicals) / Mitochondrial Proteins (NLM Chemicals) /
                      Reactive Oxygen Species (NLM Chemicals) / TRAP1 protein,
                      human (NLM Chemicals) / NAD (NLM Chemicals) / Adenosine
                      Triphosphate (NLM Chemicals) / Metformin (NLM Chemicals) /
                      Protein Kinases (NLM Chemicals) / PTEN-induced putative
                      kinase (NLM Chemicals) / Serine Endopeptidases (NLM
                      Chemicals) / HTRA2 protein, human (NLM Chemicals) /
                      High-Temperature Requirement A Serine Peptidase 2 (NLM
                      Chemicals)},
      cin          = {AG Gasser / AG Berg ; AG Berg / Ext HIH / Ext UKT /
                      Tübingen common},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000055 /
                      I:(DE-2719)5000057 / I:(DE-2719)5000058 /
                      I:(DE-2719)6000018},
      pnm          = {345 - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29050400},
      doi          = {10.1093/brain/awx202},
      url          = {https://pub.dzne.de/record/139474},
}