Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity.

Acetyl-CoA is a molecule central to cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 mutations have been linked to peripheral neuropathy, developmental delay with premature death, and intellectual disability with progeria. Here, we show that AT-1 overexpression impacts diverse phenotypes related to neuronal function and plasticity. Differences in ribosomal, synaptic processing, and metabolic pathways were identified at transcriptomic and proteomic levels. Metabolic adaptations included changes in mitochondrial membrane potential, architecture, and respiration, and tracing experiments revealed changes in the fate of glucose favoring glycogen storage over the pentose phosphate pathway. Altered redox was linked to NAD-dependent proteins SIRT1 and CtBP2. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization. Metabolic adaptation was coincident with decreased synaptic activity, indicating that neuronal communication is coordinated, in part, through acetyl-CoA metabolism.