Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Researchers identified that in Cox10 mutant mice, oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX), leading to severe neuropathy, dysmyelination, and muscle atrophy in the peripheral nervous system. However, in the adult central nervous system, no signs of demyelination or axonal degeneration were observed. Post-myelination oligodendrocytes survive well without COX activity, and brain lactate levels were increased in mutants, indicating aerobic glycolysis products are rapidly metabolized in white matter tracts. This suggests a model where axon-glia metabolic coupling serves a physiological function. The Cox10 gene encodes a haem A farnesyl transferase essential for COX assembly. In Cox10 mutants, COX is unstable and rapidly degraded. Using conditional mutagenesis, researchers generated models of mitochondrial disease in muscle, brain, and liver. They crossed Cox10flox/flox mice with Cnp1Cre/+ mice to target Schwann cells and oligodendrocytes. In the absence of functional COX, glial cells should fail to fully metabolize glucose, leading to ATP production via glycolysis and lactate generation. However, no signs of demyelination or glial cell death were observed in the adult central nervous system. In the peripheral nervous system, Cox10 mutants exhibited severe neuropathy, with reduced weight, tremors, and hindlimb weakness. At P21, attempts to compare sciatic nerve conduction velocities failed, indicating conduction blocks. Mutant mice showed reduced amplitude of compound muscle action potentials, indicating glial and axonal perturbations. By morphology and TUNEL staining, no evidence of Schwann cell death was found. However, the number of cell nuclei was increased, and mutant nerves were thinner with reduced myelinated axons. In the brain and spinal cord, myelinated tracts were normally developed at 2 months of age, suggesting sufficient respiration of oligodendroglial mitochondria during myelination. At 9 months, no signs of white matter pathology, demyelination, or oligodendroglial pathology were observed, despite the absence of COX activity in oligodendrocyte lineage cells. Mature oligodendrocytes showed abnormal mitochondrial expansion but were COX-negative. Using localized proton magnetic resonance spectroscopy, researchers found increased brain lactate levels in Cox10 mutants, indicating aerobic glycolysis products are rapidly metabolized in white matter tracts. This supports a model where oligodendrocytes supply lactate to myelinated axons, which can use it as an energy source when energy-deprived. The study highlights the role of glycolyticGlycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Researchers identified that in Cox10 mutant mice, oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX), leading to severe neuropathy, dysmyelination, and muscle atrophy in the peripheral nervous system. However, in the adult central nervous system, no signs of demyelination or axonal degeneration were observed. Post-myelination oligodendrocytes survive well without COX activity, and brain lactate levels were increased in mutants, indicating aerobic glycolysis products are rapidly metabolized in white matter tracts. This suggests a model where axon-glia metabolic coupling serves a physiological function. The Cox10 gene encodes a haem A farnesyl transferase essential for COX assembly. In Cox10 mutants, COX is unstable and rapidly degraded. Using conditional mutagenesis, researchers generated models of mitochondrial disease in muscle, brain, and liver. They crossed Cox10flox/flox mice with Cnp1Cre/+ mice to target Schwann cells and oligodendrocytes. In the absence of functional COX, glial cells should fail to fully metabolize glucose, leading to ATP production via glycolysis and lactate generation. However, no signs of demyelination or glial cell death were observed in the adult central nervous system. In the peripheral nervous system, Cox10 mutants exhibited severe neuropathy, with reduced weight, tremors, and hindlimb weakness. At P21, attempts to compare sciatic nerve conduction velocities failed, indicating conduction blocks. Mutant mice showed reduced amplitude of compound muscle action potentials, indicating glial and axonal perturbations. By morphology and TUNEL staining, no evidence of Schwann cell death was found. However, the number of cell nuclei was increased, and mutant nerves were thinner with reduced myelinated axons. In the brain and spinal cord, myelinated tracts were normally developed at 2 months of age, suggesting sufficient respiration of oligodendroglial mitochondria during myelination. At 9 months, no signs of white matter pathology, demyelination, or oligodendroglial pathology were observed, despite the absence of COX activity in oligodendrocyte lineage cells. Mature oligodendrocytes showed abnormal mitochondrial expansion but were COX-negative. Using localized proton magnetic resonance spectroscopy, researchers found increased brain lactate levels in Cox10 mutants, indicating aerobic glycolysis products are rapidly metabolized in white matter tracts. This supports a model where oligodendrocytes supply lactate to myelinated axons, which can use it as an energy source when energy-deprived. The study highlights the role of glycolytic