TY - JOUR
T1 - Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
AU - Fitzgerald, Julia C.
AU - Zimprich, Alexander
AU - Berrio, Daniel A.Carvajal
AU - Schindler, Kevin M.
AU - Maurer, Brigitte
AU - Schulte, Claudia
AU - Bus, Christine
AU - Hauser, Anne 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
N1 - Publisher Copyright:
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
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 - Experimental models
KW - Metabolic disease
KW - Mitochondrial diseases
KW - Neuroprotection
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85031772069&partnerID=8YFLogxK
U2 - 10.1093/brain/awx202
DO - 10.1093/brain/awx202
M3 - Article
C2 - 29050400
AN - SCOPUS:85031772069
SN - 0006-8950
VL - 140
SP - 2444
EP - 2459
JO - Brain
JF - Brain
IS - 9
ER -