Fitzgerald Brain 2017.pdf (363.15 kB)
Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
journal contributionposted on 2017-11-21, 11:13 authored by Julia C. Fitzgerald, Alexander Zimprich, Daniel A. Carvajal Berrio, Kevin M. Schindler, Brigitte Maurer, Claudia Schulte, Christine Bus, Anne-Katrin Hauser, Manuela Kübler, Rahel Lewin, Dheeraj Reddy Bobbili, Lisa M. Schwarz, Evangelia Vartholomaiou, Kathrin Brockmann, Richard Wüst, Johannes Madlung, Alfred Nordheim, Olaf Riess, L. Miguel Martins, Enrico Glaab, Patrick May, Katja Schenke-Layland, Didier Picard, Manu Sharma, Thomas Gasser, Rejko Krüger
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.
The project underlying this publication was funded by the German Federal Ministry of Education and Research (BMBF) under the support code 031 A 430 A. This work was further supported by grants from the Luxembourg National Research Fund (FNR) within the National Centre of Excellence in Research on Parkinson's disease (NCER-PD), PEARL programme (FNR; FNR/P13/6682797 to R.K.), the German Research Council (DFG; KR2119/8-1 to R.K. and T.G.), the EU Joint Program-Neurodegenerative Diseases (JPND; COURAGE-PD) and by the European Union's Horizon2020 research and innovation program under grant agreement No 692320 (WIDESPREAD; CENTRE-PD). T.G. and C.B. gratefully acknowledge the support of the Eva Thies Stiftung. E.G. acknowledges FNR support by grant C13/BM/5782168. K.S.L. acknowledges support by the Ministry of Science, Research and the Arts of Baden-Württemberg (33-729.55-3/214 and SI-BW 01222-91), and the Deutsche Forschungsgemeinschaft (INST 2388/30-1). E.V. and D.P. were supported by the Swiss National Science Foundation. Bioinformatics analyses presented in this paper were carried out in part using the HPC facilities of the University of Luxembourg (see http://hpc.uni.lu). PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including Abbvie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeek, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Servier, Teva, UCB, and Golub Capital.
CitationBrain, 2017, 140(9), pp. 2444-2459 (16)
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/MBSP Non-Medical Departments/Molecular & Cell Biology
- AM (Accepted Manuscript)
PublisherOxford University Press (OUP) for Guarantors of Brain
NotesSupplementary material is available at Brain online.;The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.
Science & TechnologyLife Sciences & BiomedicineClinical NeurologyNeurosciencesNeurosciences & Neurologymitochondrial diseasesParkinson's diseasemetabolic diseaseneuroprotectionexperimental modelsUNFOLDED PROTEIN RESPONSEHUMAN OVARIAN-CANCERCHAPERONE TRAP1METABOLIC SWITCHCOMPLEX 1HTRA2CELLSPHOSPHORYLATIONINHIBITIONOMI/HTRA2