Reference : Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in...
Scientific journals : Article
Life sciences : Biotechnology
Life sciences : Multidisciplinary, general & others
Human health sciences : Neurology
Systems Biomedicine
Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C. [> >]
Zimprich, Alexander [> >]
Carvajal-Berrio, Daniel A. [> >]
Schindler, Kevin M. [> >]
Maurer, Brigitte [> >]
Schulte, Claudia [> >]
Bus, Christine [> >]
Hauser, Anne-Kathrin [> >]
Kübler, Manuela [> >]
Lewin, Rahel [> >]
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Schwarz, Lisa M. [> >]
Vartholomaiou, Evangela [> >]
Brockmann, Kathrin [> >]
Wüst, Richard [> >]
Madlung, Johannes [> >]
Nordheim, Alfred [> >]
Riess, Olaf [> >]
Martins, L. Miguel [> >]
Glaab, Enrico mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Schenke-Layland, Katja [> >]
Picard, Didier [> >]
Sharma, Manu [> >]
Gasser, Thomas [> >]
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Brain : A Journal of Neurology
Oxford University Press
Yes (verified by ORBilu)
United Kingdom
[en] mitochondrial diseases ; Parkinson's disease ; metabolic disease ; neuroprotection ; experimental models ; unfolded protein response ; TRAP1 ; mutation ; bioinformatics ; genetics ; sequencing
[en] 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 signaling is unclear. 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Fonds National de la Recherche - FnR ; German Ministry of Education (BMBF) ; EU Joint Programme - Neurodegenerative Disease Research (JPND) ; German Research Council
Researchers ; Professionals ; Students ; General public
FnR ; FNR5782168 > Enrico Glaab > ExPDIENT > Exploring Parkinson’S Disease Inhibitor Efficacy On A Non-Dopaminergic Target > 01/12/2013 > 31/05/2016 > 2013

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