Oligodendroglial fatty acid metabolism as a central nervous system energy reserve
Nature Neuroscience volume 27, pages 1934–1944 (2024 )Cite this article
Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.
In the central nervous system of vertebrates, oligodendrocytes make myelin to enable saltatory impulse conduction1. Myelinating oligodendrocytes also provide fast spiking axons with lactate or pyruvate2,3,4 for the generation of ATP5. This metabolic support of axonal projections by the associated glial cells has preceded the evolution of myelin in vertebrates6,7, but is most important when myelin deprives axons from access to metabolites of the extracellular milieu. In nonmyelinating species, axon-associated glial cells also harbor lipid droplets8, which can serve as local energy reserves by mobilizing fatty acids (FAs) under starvation conditions9.
