Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity
Abstract
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.
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BibTeX
@article{mcgregor2026overexpression,
title = {{Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity}},
author = {Eric R. McGregor and Cassandra J. McGill and Nicholas L. Arp and Josef P. Clark and Dominique A. Baldwin and Yusi Cui and Alexander Nassar and Di Kuang and Gonzalo Fernandez-Fuente and Yun Hwa Choi and Keenan S. Pearson and Jason K. Nagorski and Lingjun Li and Judith A. Simcox and Jing Fan and Luigi Puglielli and Rozalyn M. Anderson},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117722},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03103-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Overexpression of endoplasmic reticulum acetyl-CoA transporter AT-1 alters neuronal metabolism, growth, and synaptic activity
AU - Eric R. McGregor
AU - Cassandra J. McGill
AU - Nicholas L. Arp
AU - Josef P. Clark
AU - Dominique A. Baldwin
AU - Yusi Cui
AU - Alexander Nassar
AU - Di Kuang
AU - Gonzalo Fernandez-Fuente
AU - Yun Hwa Choi
AU - Keenan S. Pearson
AU - Jason K. Nagorski
AU - Lingjun Li
AU - Judith A. Simcox
AU - Jing Fan
AU - Luigi Puglielli
AU - Rozalyn M. Anderson
PY - 2026
DA - 2026/10/14
JO - iScience
DO - 10.1016/j.isci.2026.117722
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03103-2
AB - 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.
SN - 2589-0042
ER -