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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Leire Izagirre-Urizar,
  • Luna Mora-Huerta,
  • Irene Soler-Saez,
  • Raquel Morales-Gallel,
  • Mary-Amélie Masson,
  • Maria-Jose Ulloa-Navas,
  • Juan-Carlos Chara,
  • Stefano Calovi,
  • Cyrille Deboux,
  • Laura Merino-Cacho,
  • Maria Andrés-Bilbao,
  • Alejandro Carretero-Guillén,
  • Citlalli Netzahualcoyotzi,
  • Maria Domercq,
  • José L. Zugaza,
  • Luc Pellerin,
  • Francisco Garcia-Garcia,
  • Jose-Manuel Garcia-Verdugo,
  • Carlos Matute,
  • Brahim Nait-Oumesmar,
  • Vanja Tepavčević

摘要

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.