Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Abstract

After myelination, oligodendrocytes are able to survive without mitochondrial respiration, suggesting that they can switch to aerobic glycolysis and release lactate. In the central nervous system, the myelin sheath that insulates and protects the axon is produced by glial cells known as oligodendrocytes. A study of conditional mutant mice in which myelin-producing cells fail to assemble mitochondrial cytochrome c oxidase complex IV shows, surprisingly, that the oligodendrocytes continued to support myelination in the absence of mitochondrial respiration. They seem to be able to switch to lactate-producing aerobic glycolysis. And because myelinated axons can utilize lactate when energy-deprived, this may be an extra means by which the oligodendrocytes support functioning axons. Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity1,2,3. However, the underlying support mechanisms are not understood4. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors5, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived6, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.