TY  - JOUR
AU  - Fitzgerald, Julia
AU  - Zimprich, Alexander
AU  - Carvajal Berrio, Daniel A
AU  - Schindler, Kevin M
AU  - Maurer, Brigitte
AU  - Schulte, Claudia
AU  - Bus, Christine
AU  - Hauser, Ann-Kathrin
AU  - Kübler, Manuela
AU  - Lewin, Rahel
AU  - Bobbili, Dheeraj Reddy
AU  - Schwarz, Lisa M
AU  - Vartholomaiou, Evangelia
AU  - Brockmann, Kathrin
AU  - Wüst, Richard
AU  - Madlung, Johannes
AU  - Nordheim, Alfred
AU  - Riess, Olaf
AU  - Martins, L Miguel
AU  - Glaab, Enrico
AU  - May, Patrick
AU  - Schenke-Layland, Katja
AU  - Picard, Didier
AU  - Sharma, Manu
AU  - Gasser, Thomas
AU  - Krüger, Rejko
TI  - Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease.
JO  - Brain
VL  - 140
IS  - 9
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-05796
SP  - 2444-2459
PY  - 2017
AB  - 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.
KW  - Adenosine Triphosphate: metabolism
KW  - Apoptosis: drug effects
KW  - Case-Control Studies
KW  - Cells, Cultured
KW  - Fibroblasts: metabolism
KW  - HSP90 Heat-Shock Proteins: biosynthesis
KW  - HSP90 Heat-Shock Proteins: genetics
KW  - High-Temperature Requirement A Serine Peptidase 2
KW  - Humans
KW  - Membrane Potential, Mitochondrial: physiology
KW  - Metformin: therapeutic use
KW  - Mitochondria: drug effects
KW  - Mitochondria: genetics
KW  - Mitochondria: metabolism
KW  - Mitochondrial Proteins: metabolism
KW  - Mutation
KW  - NAD: metabolism
KW  - Organelle Biogenesis
KW  - Oxygen Consumption
KW  - Parkinson Disease: drug therapy
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - Protein Kinases: metabolism
KW  - Reactive Oxygen Species: metabolism
KW  - Serine Endopeptidases: metabolism
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - Mitochondrial Proteins (NLM Chemicals)
KW  - Reactive Oxygen Species (NLM Chemicals)
KW  - TRAP1 protein, human (NLM Chemicals)
KW  - NAD (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - Metformin (NLM Chemicals)
KW  - Protein Kinases (NLM Chemicals)
KW  - PTEN-induced putative kinase (NLM Chemicals)
KW  - Serine Endopeptidases (NLM Chemicals)
KW  - HTRA2 protein, human (NLM Chemicals)
KW  - High-Temperature Requirement A Serine Peptidase 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29050400
DO  - DOI:10.1093/brain/awx202
UR  - https://pub.dzne.de/record/139474
ER  -