Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity

Area of Science:

• Neuroscience
• Cellular Metabolism
• Molecular Biology

Background:

• Acetyl-CoA is crucial for metabolic homeostasis and is transported into the endoplasmic reticulum by AT-1 (SLC33A1).
• AT-1 dysfunction is associated with neurological disorders, including neuropathy and intellectual disability.
• Previous studies show AT-1 mutations can be replicated in mouse models.

Purpose of the Study:

• To investigate the impact of AT-1 overexpression on neuronal function and plasticity.
• To explore the molecular and functional consequences of altered acetyl-CoA transport in neurons.

Main Methods:

• Transcriptomic and proteomic analysis of primary neurons with AT-1 overexpression.
• Assessment of mitochondrial function, including membrane potential, architecture, and respiration.
• Metabolic tracing experiments to analyze glucose utilization and lipid metabolism.
• Analysis of redox metabolism and protein acetylation.

Main Results:

• AT-1 overexpression induced brain aging signatures and altered ribosomal and synaptic processes.
• Mitochondrial pathways were upregulated, indicated by increased PGC-1α expression, with functional changes in mitochondrial potential, architecture, and respiration.
• Altered glucose utilization, shifts in redox metabolism, and depletion of lipid stores were observed.
• Reduced synaptic protein expression and synaptic network activity were linked to altered neuronal acetyl-CoA metabolism.

Conclusions:

• Neuronal acetyl-CoA metabolism significantly influences neuronal electrophysiology and network communication.
• AT-1 plays a critical role in maintaining neuronal function and plasticity.
• Dysregulation of AT-1 impacts multiple cellular processes, contributing to neuronal dysfunction and potentially aging-related phenotypes.