Title: Metabolic requirements of formation and maintenance of myelin around peripheral nerves
Legend: We have tested if mitochondrial substrates of Acetyl CoA generation (e.g. glucose-derived pyruvate, amino acids, fatty acids) are required for lipid synthesis in myelinating Schwann cells using a knockout of the ATP citrate lyase. A & A’) PPD-stained femoral motor nerve from 5-wk-old control (A) and Acly cKO (A’) mice; scale bar = 20µm. C-D) Electron Microscopy (1600X) of femoral motor nerve from 5-wk-old control (C) and Acly cKO (D) mice; scale bar = 8µm. Arrows and arrowheads point to amyelinated and thinly myelinated axons, respectively. E) TEM image (3400X) of “onion bulb” morphology in Acly cKO nerve; scale bar = 2µm. F) TEM image (3400X) of additional examples of pathology – thinly myelinated axon (top) and amyelinated axon (bottom) – in Acly cKO nerves; scale bar = 2µm.
Citation: Schneider, A., Won, S., Armstrong, E. A., Cooper, A. J., Suresh, A., Rivera, R., Barrett-Wilt, G., Denu, J. M., Simcox, J. A., & Svaren, J. (2025). The role of ATP citrate lyase in myelin formation and maintenance. Glia, 73(1), 105–121. https://doi.org/10.1002/glia.24620
Abstract: Formation of myelin by Schwann cells is tightly coupled to peripheral nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, yet one unresolved matter is how acetyl CoA, a central metabolite in lipid formation is generated during myelin formation and maintenance. Recent studies have shown that glucose-derived acetyl CoA itself is not required for myelination. However, the importance of mitochondrially-derived acetyl CoA has never been tested for myelination in vivo. Therefore, we have developed a Schwann cell-specific knockout of the ATP citrate lyase (Acly) gene to determine the importance of mitochondrial metabolism to supply acetyl CoA in nerve development. Intriguingly, the ACLY pathway is important for myelin maintenance rather than myelin formation. In addition, ACLY is required to maintain expression of a myelin-associated gene program and to inhibit activation of the latent Schwann cell injury program.
Investigator: John Svaren, PhD
About the Lab: The Svaren laboratory is focused on the transcriptional and epigenetic regulation of myelination. Myelin is a vital constituent of the nervous system that increases the speed of action potentials and also provides trophic support for the long axons that project from neurons. Their studies are centered on the myelin-producing cells of the peripheral nervous system, called Schwann cells. The Svaren lab has focused on elucidating regulation of gene networks during Schwann cell development and response to injury. They have also recently found a novel role of the polycomb repressive complex 2, an epigenetic regulator, in controlling the regenerative responses of Schwann cells after peripheral nerve injury.