Myelin lipids as nervous system energy reserves

Abstract

Neuronal functions and impulse propagation depend on the continuous supply of glucose1,2. Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules3. Oligodendrocytes make myelin for rapid axonal impulse conduction4 and also support axons metabolically with lactate5-7. Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases8 with underlying hypometabolism9.

Glycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation

“…The primary function of myelin is thought to be insulation of the axon, to allow fast signal conduction. Interestingly, Asadollahi et al show that myelin can also be used as energy storage under conditions of carbohydrate restriction 37 . Here, mouse oligodendrocytes use β-oxidation to maintain energy homeostasis in the optic nerve at the expense of myelin thickness.…”

“…Here, mouse oligodendrocytes use β-oxidation to maintain energy homeostasis in the optic nerve at the expense of myelin thickness. Also, oligodendrocyte-specific knockout of Glut1, limiting glucose uptake, leads to a reduction in myelin thickness in vivo 37 . In addition, MRI scans of patients suffering from anorexia nervosa show a loss of white matter, indicating that severe nutrient restriction in humans can also cause oligodendrocytes to metabolize lipids stored in the myelin sheath to maintain cerebral energy homeostasis 38,39 .…”

Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis

“…For constant myelination to occur, there needs to be a constant synthesis of lipids which are supplied by oligodendrocytes. Lipid metabolites can also serve as energy reserves when facing low glucose conditions [ 91 ]. The autophagy-lysosomal pathway is responsible for recycling myelin lipids which results in the release of fatty acids that can be used to produce new myelin lipids [ 69 ].…”

The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases

“…In addition, under conditions of significant energy restriction, oligodendrocytes assist axons by metabolizing myelin lipids via βOX and production of KBs. Studies conducted on a mouse optic nerve model demonstrated that generating ATP from lipids allows for greater allocation of glucose-derived metabolites to the axons, thereby preserving them [ 41 ]. Increased FAO levels were demonstrated in microglia during glucose deprivation.…”