Mitochondria and Powering the Mind: Secrets of Synaptic Energy with VAP

Mitochondria and Powering the Mind: Secrets of Synaptic Energy with VAP

VAP spatially stabilizes mitochondria to locally support synaptic plasticity.

WMS Analysis

The study highlights the essential role of VAP (vesicle-associated membrane protein-associated protein) in synaptic plasticity by stabilizing mitochondria near synapses through cytoskeletal tethering. VAP's ability to maintain mitochondrial stability is crucial for meeting the high energy demands of synaptic activity, facilitating memory formation and learning. This stabilization not only supports the immediate demands of synaptic plasticity but also acts as a determinant for the spatial extent of dendritic segments involved in these processes. The implications of these findings extend to understanding the mechanisms underlying neurodegenerative diseases like ALS, where disruptions in mitochondrial stability at synapses could contribute to disease pathology. Essentially, the research underscores the critical interplay between mitochondrial stability, synaptic plasticity, and the potential for targeted therapies in neurodegenerative diseases.

About the study

The study investigates the crucial role of synapses in plasticity and memory formation, highlighting that synapses, being energy consumption hotspots, depend on local energy supplies provided by mitochondria. These mitochondria are stabilized near synapses by the cytoskeleton, a necessary arrangement for supporting synaptic plasticity. The research identifies proteins that exclusively tether mitochondria to the actin near postsynaptic spines, with a focus on VAP (vesicle-associated membrane protein-associated protein), known for its implications in amyotrophic lateral sclerosis (ALS). VAP is shown to stabilize mitochondria via actin near the spines, playing a vital role in maintaining mitochondrial compartments that locally support synaptic plasticity.

The study elaborates on the necessity of local energy sources for synapses, given their distance from the neuron's cell body and high energy demands. It was previously established that mitochondria form temporally and spatially stable compartments by tethering to the cytoskeleton, which are crucial for fueling synaptic plasticity. However, the mechanisms enabling these stable mitochondrial compartments in dendrites were not fully understood.

This research provides significant insights by identifying the role of VAP in stabilizing dendritic mitochondria, ensuring their function during long durations of synaptic plasticity formation and maintenance. VAP's unique role includes acting as a spatial stabilizer and a ruler, determining the extent of dendritic segments supported during synaptic plasticity, crucial for clustered synaptic plasticity related to learning and development.

Furthermore, the study underscores the broader implications of mitochondrial dysfunction in neurodegenerative diseases like Alzheimer's, Parkinson's Disease (PD), and ALS. By leveraging advances in proteomic labeling and high-resolution imaging techniques, the research delineates the mechanisms dictating the spatial organization of dendritic mitochondria and their pivotal role in sustaining synaptic plasticity. The findings emphasize VAP's distinct role in spatially stabilizing mitochondria in dendrites, influencing both the formation and maintenance of synaptic plasticity and potentially offering new avenues for understanding and treating neurodegenerative diseases.

Article DOI.

Photo Credits: Bapat, O., Purimetla, T., Kruessel, S. et al. Nat Commun15, 205 (2024).

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