Oligodendrocyte Bioenergetics in Health and Disease

Abstract

The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person's total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.

Keywords: bioenergetics; multiple sclerosis; neurodegeneration; oligodendrocytes; remyelination.

Figure 1.

Mechanisms of energy metabolism in the myelinating oligodendrocyte (yellow). Lactate is taken up through the monocarboxylate transporter 1 (MCT1) from contact with astrocytes (red). Lactate can then be shuttled to and taken up by axons (pink) through the MCT2 on neurons. Conversely, lactate can be converted to pyruvate and transported to the mitochondria for the tricarboxylic acid (TCA) cycle or converted to ATP in the cytosol by glycolysis. Glucose can also be transported into oligodendrocytes by glucose transporters and converted to pyruvate. Small metabolites, creatine and taurine, contribute to oligodendrocyte stability. Creatine (Cr) is converted to phosphocreatine (PCr) and serves as a phosphate pool in the cytosol to aid in ATP production and promote cell survival. PCr may serve as energy source for myelin synthesis. Taurine increases serine pools to stimulate myelin synthesis within the cell.

Figure 2.

Metabolite exchange between oligodendrocyte (yellow) and axons (pink) in health and disease. In the healthy CNS, oligodendrocyte-axon coupling allows for bidirectional exchange of metabolites. In multiple sclerosis (MS), damage to myelin, axonal dystrophy, and dying back of oligodendrocytes leads to disrupted oligodendrocyte-axon coupling and impaired metabolite exchange. Figure created in BioRender.

Figure 3.

Uptake of taurine in oligodendrocyte precursor cells (OPCs) promotes differentiation and myelin synthesis. Taurine increases serine pools which enhances oligodendrocyte differentiation and promotes glycosphingolipid synthesis. Glycosphingolipid biosynthesis is essential for myelin synthesis. Figure created in BioRender.

Figure 4.

Creatine increases mitochondrial density in oligodendrocytes. A significant increase in mitochondria density was calculated in myelin basic protein (MBP)–positive oligodendrocytes after treatment with 100 µM creatine (CR) for 24 hours. Oligodendrocytes treated with PBS or treated with creatine plus guanidinopropionic acid (GPA), a competitive antagonist to the creatine transporter, showed similar mitochondrial density. Modified from Chamberlain and others (2017).

Figure 5.

Neuronal-derived N-acetylacetate (NAA) promotes myelin synthesis and energy production in oligodendrocytes (yellow). NAA is synthesized in neurons (pink) from acetyl-CoA and aspartate by aspartate N-acetyltransferase (Asp-NAT). In oligodendrocytes, NAA is metabolized by aspartoacylase (ASPA) into acetate and aspartate, which are used for myelin synthesis and energy production via the malate-aspartate shuttle (Mal-Asp shuttle), respectively. Figure created in BioRender.

Figure 6.

Biotin promotes myelin synthesis and energy production by acting as a coenzyme in oligodendrocytes (yellow) and neurons (pink). In oligodendrocytes, biotin (green) binds with acetyl-CoA carboxylase (ACC1 and ACC2) (blue) and increases the availability of fatty acids, allowing increased myelin synthesis. In neurons, biotin binds tricarboxylic acid (TCA) cycle enzymes (pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase) (purple) and increases production of TCA cycle intermediates, increasing ATP production and reducing neuronal hypoxia. Figure created in BioRender.