Oligodendroglia: metabolic supporters of neurons

Abstract

Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic "myelinic" channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.

Figure 1. Astrocyte-oligodendrocyte-neuron lactate shuttle.

Astrocytes (top) can take up glucose from the blood circulation through glucose transporters (GLUT1), a process that is enhanced upon glutamate release from neurons and glutamate binding to astrocyte-expressed glutamate transporters (GLT-1). Glycolysis breaks down glucose to pyruvate with the production of ATP and NADH. Alternatively, astrocytes can break down intracellular glucose, which is stored as glycogen. Subsequently, pyruvate is either metabolized in the mitochondria (leading to additional production of ATP) or converted to lactate by lactate dehydrogenase (LDH) when oxygen is limited (ensuring the continuation of glycolysis through oxidation of NADH to NAD⁺ to resupply the NAD⁺ pool). In oligodendrocytes (bottom), glucose can similarly be processed into pyruvate and lactate. Oligodendrocyte glucose uptake is controlled by glutamate binding to the NMDA receptor expressed on the oligodendrocyte surface. Intracellular lactate in astrocytes or oligodendrocytes can either exit the cell through the monocarboxylate transporters MCT1 and MCT4 or be converted back to pyruvate in the mitochondria, where it fuels ATP or fatty acid synthesis. Extracellular lactate can be shuttled to neurons through neuronal MCT2 and used to fuel neuronal ATP synthesis in the mitochondria. Gap junction coupling (Cx) between glial cells and glial cells/neurons mediates the exchange of metabolites like pyruvate and lactate, but the importance of these connections in metabolic shuttling is still to be further explored. Alternatively, it is hypothesized that extracellular lactate is imported in glial cells and could contribute to ATP synthesis in glial cells upon conversion to pyruvate in the mitochondria.

Figure 2. Oligodendrocytes provide metabolic support to neurons.

(A) Normal myelin with compacted (dark blue) and uncompacted (light blue) channels form a multilamellar structure around the axon. (B) In PLP-null animals, myelin appears to be ultrastructurally normal, but the underlying axons show signs of degeneration. (C) In MBP-null mice (shiverer mice), only a thin sheath of uncompacted myelin wraps the axon. Despite this dysmyelination, these mice develop normally and axons are intact. (D) The myelin in CNPase-null mice is more compacted than normal as a result of the loss of the uncompacted myelinic channels, resulting in severe axonal degeneration. (E) Loss of MCT1 in oligodendrocytes leads to axonal degeneration despite normal-appearing myelin wrapping the axons. All these models show a clear distinction between the ability of myelin to support axonal conductance and its ability to provide trophic support to the axon. How myelinic channels are affected in the PLP- and MCT1-null mice remains to be elucidated.

Figure 3. Glial cells provide metabolic support to neurons.

(i) At the synapse, neuronal activity releases glutamate (Glu) in the extracellular space, which is taken up by astrocytic GLT-1. Glutamate uptake drives glucose (Glc) uptake through glucose transporters (GLUT1) in astrocytes; glucose is subsequently converted to pyruvate (Pyr) and lactate (Lac). Intracellular lactate can be shuttled to neurons through astrocyte MCT1 and MCT4 and neuronal MCT2. Neuronal lactate can fuel neuronal ATP synthesis in the mitochondria after conversion to pyruvate. (ii) Astrocytes contact neurons at the nodes of Ranvier, and can shuttle metabolic substrates through astrocytic MCT1 and MCT4. Neurons can take up these substrates through MCT2, using them to fuel mitochondrial ATP synthesis. (iii) Oligodendrocyte myelin consists of compacted and uncompacted regions. The latter allow for transport of metabolites within the myelin, toward the adaxonal (nearest to the axon) myelin inner tongue, from where metabolites can be transported to neurons. (iv) Transport occurs through MCT1 expressed at the adaxonal oligodendrocyte process and moves substrates into the periaxonal space, where metabolites can be taken up by neurons through MCT2 and processed for ATP synthesis. (v) The metabolic supportive function of oligodendrocytes is regulated by glutamate binding to the NMDA receptor, followed by enhanced oligodendrocyte glucose uptake and conversion of glucose to lactate, which can then be provided to the neurons. (vi) Another potential source of oligodendrocyte lactate is through gap junction coupling with astrocytes. Whether metabolic supply through this pathway is essential for neuronal metabolic support remains to be determined.