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.
Highlights
Parkinson disease is an etiologically heterogeneous syndrome caused by a combination of genetic and environmental risk factors
We observe a significantly reduced ratio of succinate dehydrogenase (SDH) to cytochrome c oxidase (COX mtDNA-encoded subunit) in both R47X patient fibroblasts and TRAP1 knockout mouse adult fibroblasts (MAFs) compared to controls (Figure 5E left and middle panel), which indicates an imbalance between nuclear and mitochondrially encoded mitochondrial proteins, likely induced by the increased NAD+ and NADH pool and in agreement with the effect of NAD+ boosters on the age associated metabolic decline and promotion of longevity in worms (Mouchiroud et al, 2013)
The biochemistry of the interaction is non-canonical and does not involve the protease activity of HtrA2, leaving us to speculate that HtrA2 and TRAP1 perform in a common intramitochondrial chaperoning or quality control system
Summary
Parkinson disease is an etiologically heterogeneous syndrome caused by a combination of genetic and environmental risk factors. Mitochondrial dysfunction, ensuing cellular energy failure and oxidative stress may be one important disease pathway in a subgroup of Parkinson’s disease patients (Kruger et al, 2017). TRAP1 (tumor necrosis factor type 1 receptor associated protein, known as HSP 75) is a chaperone that resides in the mitochondrial matrix (Altieri et al, 2012). It has a regulatory role in stress sensing in mitochondria allowing cellular adaption to the environment. PINK1 has previously been shown to be required for the phosphorylation of the mitochondrial protease and Parkinson’s disease-associated protein HtrA2 (Plun-Favreau et al, 2007). We highlight a signaling pathway involving PINK1, HtrA2 and TRAP1, where TRAP1 is the effector modulating mitochondrial chaperone activities and metabolic homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
