Monocarboxylate transporter 2 regulates maintenance of myelin and axonal integrity by oligodendrocytes

Myelin alterations, tightly linked to axonal degeneration, are common in neurodegenerative diseases, including multiple sclerosis (MS). However, the metabolic mechanisms that sustain white matter integrity remain elusive. Monocarboxylates are important energy fuels, but their role in myelinating oligodendrocyte function remains unclear. Here, we show that myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2), which is downregulated in progressive MS. While deletion of MCT2 in the mouse spinal white matter using oligodendrotropic AAV injection does not affect oligodendrocyte survival, it downregulates lipid synthesis-associated enzymes and increases inflammation, leading to a failure of myelin maintenance. These changes, not evidenced in AAV-control mice that only show mild inflammation, are accompanied by axonal upregulation of lactate dehydrogenase A and injury, effects alleviated by ketogenic diet. Therefore, our findings show that oligodendroglial MCT2 regulates myelin maintenance and axonal support under mild inflammation. This appears disrupted in progressive MS but might be compensated for by specific metabolic therapies to preserve white matter integrity. Metabolic determinants of white matter integrity remain elusive. Here, the authors show downregulation of MCT2 in oligodendrocytes in progressive MS, and then demonstrate its role in myelin maintenance in mice, where the effects of MCT2 loss can be alleviated by a ketogenic diet.