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|Title:||Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease|
|Authors:||Fitzgerald, Julia C.|
Berrio, Daniel A. Carvajal
Schindler, Kevin M.
Bobbili, Dheeraj Reddy
Schwarz, Lisa M.
Martins, L. Miguel
|Publisher:||Oxford University Press (OUP) for Guarantors of Brain|
|Citation:||Brain, 2017, 140(9), pp. 2444-2459 (16)|
|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.|
|Embargo on file until:||1-Sep-2018|
|Rights:||Copyright © 2017, Oxford University Press (OUP) for Guarantors of Brain. Deposited with reference to the publisher’s open access archiving policy.|
|Description:||Supplementary 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.
|Appears in Collections:||Published Articles, Dept. of Molecular and Cell Biology|
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