What are the key mechanisms of control and transport of ATP from mitochondria to synapse in active firing neurons?

Question

I am working with a group in the field of neuronal activity (in computational neuroscience), in specific the firing rates at different ensemble/population hierarchies.

It is well established that neuronal activity, particularly in the synaptic areas, is energy-intensive, and ATP consuming. There is vast scientific research literature on the molecular mechanisms of how ATP in the membrane area of synapses is being processed. However, in contrast, there is a challenge to understand the molecular mechanisms of how the synaptic cellular membrane regions communicate at the neuron's molecular level with the mitochondria to ensure tight energy control. There are two central questions which I want to understand:

1. How and by which mechanisms, at the molecular level, the synaptic areas of the membrane ensure an efficient system control of ATP delivery adapting to the neuronal activity requirements.
2. The mechanism of transport of ATP from mitochondria to the synaptic regions of the cell membrane.

I would appreciate comprehensive information on both aspects. The answer should optimally:

• describe the key molecular mechanisms at a high-level,
• including clearly key and major steps of the control and transport process, and
• referring to scientific reference papers for further detailed insights.

Research results must not be focused on human neurons, and can be on model organisms or cells.

Thank you in advance.

Answer 1

Synapses are full of mitochondria - Palay, S. L. (1956). Synapses in the central nervous system. The Journal of biophysical and biochemical cytology, 2(4), 193.

So, it's not so much that ATP needs to be delivered to synapses; ATP is manufactured there. Trafficking of mitochondria to synapses is regulated by neuronal activity, see for example:

Sheng, Z. H., & Cai, Q. (2012). Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nature Reviews Neuroscience, 13(2), 77-93.

This review talks about kinesin and dynein motors that are involved in this transport along microtubules. Like many other aspects of neural transmission, mitochondrial transport is regulated at least in part through calcium concentrations. Like other elements of the synaptic machinery, mitochondria are anchored to synaptic protein complexes which keeps them in place. The more places to dock, the greater eventual concentration of everything in the synapse. Additionally, both calcium and ADP concentration slow down mitochondrial transport and can lead to a process where mitochondria stop moving around and settle where they are needed. Calcium concentration is increased when synapses are active, and ADP is high when ATP is being used, so both of those signals cause mitochondria to "stop" when they pass by an area that needs more ATP production, and keep on moving through otherwise.

Other relevant reviews:

Misgeld, T., & Schwarz, T. L. (2017). Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron, 96(3), 651-666.

Devine, M. J., & Kittler, J. T. (2018). Mitochondria at the neuronal presynapse in health and disease. Nature Reviews Neuroscience, 19(2), 63-80.

Rossi, M. J., & Pekkurnaz, G. (2019). Powerhouse of the mind: mitochondrial plasticity at the synapse. Current opinion in neurobiology, 57, 149-155..