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ERC

SynapticMitochondria Report Summary

Project ID: 679168
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - SynapticMitochondria (Quality Control and Maintenance of Synaptic Mitochondria)

Reporting period: 2016-09-01 to 2018-02-28

Summary of the context and overall objectives of the project

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. My 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 I propose to use proteomic approaches to identify the protein fingerprint of synaptic mitochondria and to compare them to mitochondria from other tissues. I plan to identify key players of the proposed regulatory pathways involved in intrinsic mitochondria quality control. In a complimentary approach, I will exploit our findings and use in vitro and in vivo experimental approaches to measure mitochondrial function of synaptic versus non-synaptic mitochondria and the relevance of those changes for synaptic function. Our work will unravel the specific properties of synaptic mitochondria and provide much needed insight in their hypothesized predominant role in neurodegenerative disorders.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.
The first aim of this research project is to identify and characterize novel components of synaptic mitochondria. For this, we have determined the proteomic profile that discriminates synaptic mitochondria from non-synaptic mitochondria, and through Bioinformatics analysis we have identified our 10 top candidate proteins. At present, we are assessing the protein expression pattern in these two distinct mitochondrial pools, as well as, the role of our candidate proteins in specific mitochondrial regulatory pathways. Additionally, we also are assessing the overall mitochondrial properties of these neuronal mitochondrial pools. For this, we are assessing cristae organization, bionenergetic profile and overall mitochondrial capacity of synaptic and non-synaptic mitochondria.
The second aim of this research project is to pinpoint mitochondrial quality control (MQC) mechanisms that synaptic mitochondria use to sense and maintain their intrinsic function. We have established reporter cell lines that will aid in understanding the cross-talk between PINK1/PARL/PGAM5.
Our integrative approach, based on using an unbiased approach and a candidate gene approach, is providing a unifying model revealing the mechanisms involved in maintaining a healthy pool of mitochondria at the synapse.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This research project will significantly advance the understanding of the role of synaptic mitochondria maintaining synapse function. This work will reveal a proteome specific to synaptic mitochondria and unravel the quality control mechanisms that regulate synaptic mitochondria in a healthy and damaged neuron. Additionally, we will have developed a unique array of methodology to evaluate the function of mitochondria in synapses which will position us in a unique way to address the many speculative links made between mitochondria and neurodegenerative disorders. Finally, if successful, this research project will identify molecular mechanisms that cause neurodegenerative disorders, which open the avenues to new therapeutic approaches.
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