Quality Control and Maintenance of Synaptic Mitochondria
Funding Agency: European Commission
Funding Programme: Horizon 2020
Call/Topic: ERC-StG-2015
Project Reference: 679168
Start Date: 2016.09.01
Duration: 60 months
Total Investment: EUR 1 300 000 (EU contribution: EUR 1 300 000)
Project Coordinator: Vanessa Morais
Project Beneficiaries: Instituto de Medicina Molecular João Lobo Antunes (iMM), Portugal
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 679168.
Overview
Mitochondria at the synapse have a pivotal role in neurotransmitter release, but almost nothing is known about synaptic mitochondria composition or specific functions. Synaptic mitochondria compared to mitochondria in other cells, need to cope with increased calcium load, more oxidative stress, and high demands of energy generation during synaptic activity. This project’s hypothesis is that synaptic mitochondria have acquired specific mechanisms to manage local stress and that disruption of these mechanisms contributes to neurodegeneration.
How mitochondria sense their dysfunction is unclear. Even more intriguing is the question how they decide whether their failure should lead to removal of the organelle or dismissal of the complete neuron via cell death. We anticipate that these decisions are not only operational during disease, but might constitute a fundamental mechanism relevant for maintenance of synaptic activity and establishment of new synapses.
Recent studies have revealed several genes implicated in neurodegenerative disorders involved in mitochondrial maintenance. However, the function of these genes at the synapse, where the initial damage occurs, remains to be clarified.
These genes provide excellent starting points to decipher the molecular mechanisms discussed above. Furthermore, we propose to use proteomic approaches to identify the protein fingerprint of synaptic mitochondria and to compare them to mitochondria from other tissues.
We plan to identify key players of the proposed regulatory pathways involved in intrinsic mitochondria quality control. In a complimentary approach, we will exploit our findings and use in vitroand in vivoexperimental approaches to measure mitochondrial function of synaptic versusnon-synaptic mitochondria and the relevance of those changes for synaptic function.
This project will unravel the specific properties of synaptic mitochondria and provide much needed insight in their hypothesized predominant role in neurodegenerative disorders.