Phosphoinositide-lipid signaling in neuronal mitochondrial biogenesis

Project Information

MitoPIP

Grant agreement ID: 101077138

DOI

10.3030/101077138

EC signature date 24 November 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 497 500,00

EU contribution

€ 1 497 500,00

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 1 - MitoPIP (Phosphoinositide-lipid signaling in neuronal mitochondrial biogenesis)

Reporting period: 2023-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

Mitochondria are the power engines of the cell. They produce energy by converting sugar and oxygen into chemical forms of energy. In our brain, nerve cells have extremely long cellular extensions, which connect individual nerve cells with each other by forming synapses. Mitochondria are moved into and strategically positioned within those projections to ensure that these connections are supplied with sufficient energy to allow neuronal communication. Consequently, mitochondrial dysfunction can lead to a number of neurological disorders. Therefore, the mechanisms by which mitochondria are replaced or removed are crucial to ensure neuronal health.
Our research has shown that mitochondria can be loaded with protein blueprints when they embark on the journey into the neuronal extensions. This allows them to have a constant supply of proteins they require for their work, even at remote locations in the nerve cell. A protein named synaptojanin 2 facilitates this supply by binding to mitochondria via an adapter protein and simultaneously associating with certain protein blueprints. One of these blueprints can be used to produce a protein called PINK1, which is important in the detection and removal of damaged mitochondria. However, synaptojanin 2 is also able to interact with and modify lipid membranes within the cell, such as the plasma membrane surrounding the cell or endosomes, which are vesicles formed by invaginations of the plasma membrane. The plasma membrane in neurons contains several receptors necessary for the communication between nerve cells. These receptors react to molecules such as neurotransmitters e.g. by opening a hole that permits the entry of Calcium ions into the cell.
Neuronal connections that receive frequent activity produce more of these receptors, strengthening the synapse and making it easier to re-activate the same connection. This process is thought to enable learning, as it creates positive reinforcement of this connection. Another aspect of memory is the ability to remove weak connections. Neurons that should not associate together can repress their communication by removing the neurotransmitter receptors from the plasma membrane by pulling them to the inside of the cell within endosomes where they cannot react to extrinsic signals. We are now asking: What happens if these endosomes come into contact with synaptojanin 2?

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

We have observed that in cultured neurons the formation of neurotransmitter receptor-containing endosomes is correlated with a transient drop in mitochondrial energy output. At the same time, we can observe the production of PINK1 from its local blueprint at mitochondria in the long neuronal extensions. PINK1 is a protein that can sense this drop of mitochondrial activity and may interpret this as mitochondrial damage. This leads to the activation of a signalling cascade, that first chops a damaged mitochondrion into smaller pieces. These small pieces can then be selectively degraded within the cell. Intriguingly, we see that indeed the induction of endosomes leads to mitochondrial fragmentation over time. Some of the smallest pieces get metabolized by the cell, as we detect less mitochondrial coverage after the induction of endosomes. This suggests that the nerve cell may also use the local production of PINK1 and the removal of mitochondria to destabilize connections that are equivalent to “wrong associations”. As the number of mitochondria correlates with the energy that a nerve cell can spend on growing new connections or on controlling the influx of ions this could be a powerful way to prevent the persistence of such unwanted connections. In addition, we report that synaptojanin 2 modulates the time Calcium ions remain inside the cell upon activation of neurotransmitter receptors, further altering the signalling mechanisms downstream of synaptic transmission and neuronal communication.
We will explore how this mechanism influences learning and memory in a more physiological context by using mice that lack synaptojanin 2 and thus may not be able to effectively prune their unwanted circuits.

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)

Diseases that are caused by an inability to effectively prune synapses include post-traumatic stress disorder, schizophrenia or bipolar disorder. We already published a connection between the metabolic state of the cell and the ability of neurons to activate PINK1 and thus removal of mitochondria. Unlike previously thought, we find that fasting prevents mitochondrial degradation in neurons. If this process also regulates the association of mitochondrial loss in the context of endosomes induced by synaptic signalling, it is conceivable that supportive dietary therapies may ensue from our research. Intriguingly, some of the medications used to treat these disorders also affect the lipid composition of membranes and thus could alter the interplay between endosomes and synaptojanin 2. This suggests that already the existing medication may target this pathway, and further mechanistic exploration may lead to improvements and innovations for therapeutic approaches.

Communication between neurons is powered by mitochondria and their number may be altered by learning