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.
Authors
- Keenan S. Pearson (ORCID: https://orcid.org/0000-0002-4504-4002)
- Judith Simcox (ORCID: https://orcid.org/0000-0001-7350-6342)
- Yun Hwa Choi (ORCID: https://orcid.org/0000-0002-9344-6110)
- Gonzalo Fernandez-Fuente (ORCID: https://orcid.org/0000-0002-7950-2112)
- Cassandra Joan McGill (ORCID: https://orcid.org/0000-0002-0524-5061)
- Yusi Cui (ORCID: https://orcid.org/0000-0003-1198-5960)
- Eric R. McGregor (ORCID: https://orcid.org/0000-0002-0537-287X)
- L. Li (ORCID: https://orcid.org/0009-0002-2282-1005)
- Nicholas L. Arp (ORCID: https://orcid.org/0000-0001-8709-0667)
- Luigi Puglielli (ORCID: https://orcid.org/0000-0003-0259-8424)
- Rozalyn M. Anderson (ORCID: https://orcid.org/0000-0002-0864-7998)
- Josef P. Clark (ORCID: https://orcid.org/0000-0003-1826-2618)
- Dominique A. Baldwin
- Alexander Nassar (ORCID: https://orcid.org/0009-0000-2215-931X)
- Jason K Nagorski
- Jing Fan
- Di Kuang
Institutions
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- Morgridge Institute for Research (US)
- William S. Middleton Memorial Veterans Hospital (US)
Publication Details
- Journal
- iScience
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1016/j.isci.2026.117722
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Federation for Aging Research
- National Institute on Aging
- NIH Office of the Director
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke