A new study identifies a novel metabolic regulator of white matter integrity disrupted in Multiple Sclerosis

Despite major advances in immunomodulatory therapies for multiple sclerosis (MS), preventing the neurodegeneration associated with disease progression remains an unmet clinical need. As in many neurodegenerative disorders, growing evidence points to profound metabolic alterations in the central nervous system of people with MS. Understanding how these energy deficits arise is essential for developing effective neuroprotective therapies.

Oligodendrocytes maintain myelin and provide crucial metabolic support to axons, yet the mechanisms that allow these cells to meet the high energy demands required for these functions remain poorly understood. In an article entitled “Monocarboxylate transporter 2 regulates maintenance of myelin and axonal integrity by oligodendrocytes”, published in Nature Communications, researchers from the ACHUCARRO, EHU and the NeuroCore group from the Universitat de València–Cavanilles Institute, led by Vanja Tepavčević, identify a previously unrecognized regulator of white matter integrity that is disrupted in MS and propose a potential strategy to alleviate this dysfunction.

The study demonstrates that oligodendrocytes express the high-affinity monocarboxylate transporter MCT2, previously known for its role in neuronal energy metabolism by enabling neurons to efficiently take up lactate supplied by astrocytes through the astrocyte–neuron lactate shuttle. The researchers found that deleting MCT2 in mouse oligodendrocytes reduced the expression of enzymes involved in lipid synthesis, increased neuroinflammation, and ultimately impaired myelin maintenance and axonal integrity.

Importantly, the authors also found that MCT2 expression is reduced in oligodendrocytes from patients with progressive MS, suggesting that these cells become metabolically compromised during disease progression. Remarkably, the axonal damage and myelin abnormalities caused by oligodendroglial MCT2 deletion in mice were ameliorated by a ketogenic diet, indicating that increasing ketone availability may represent a promising metabolic strategy to preserve myelin and axonal function in MS.

This project was carried out in collaboration with the Institut du Cerveau – Paris Brain Institute (INSERM), the Computational Biology Laboratory at the Príncipe Felipe Research Center (CIPF), and the University of Poitiers. Several authors are also affiliated with CIBERNED.

The research was supported by ARSEP/France Sclérose En Plaques, the Spanish Ministry of Science and Innovation, the Plan GenT program (Generalitat Valenciana, Conselleria d’Educació), the Basque Government (Gobierno Vasco), BIOEF, and The Walk-On Foundation.

Congratulations to all the authors, collaborators, and funding organizations who contributed to this achievement.

Read the full article here: 10.1038/s41467-026-74488-w