MCT1 Deletion in Oligodendrocyte Lineage Cells Causes Late-Onset Hypomyelination and Axonal Degeneration

Oligodendrocytes (OLs) are important for myelination and shuttling energy metabolites lactate and pyruvate toward axons through their expression of monocarboxylate transporter 1 (MCT1). Recent studies suggest that loss of OL MCT1 causes axonal degeneration. However, it is unknown how widespread and chronic loss of MCT1 in OLs specifically affects neuronal energy homeostasis with aging. To answer this, MCT1 conditional null mice were generated that allow for OL-specific MCT1 ablation. We observe that MCT1 loss from OL lineage cells is dispensable for normal myelination and axonal energy homeostasis early in life. By contrast, loss of OL lineage MCT1 expression with aging leads to significant axonal degeneration with concomitant hypomyelination. These data support the hypothesis that MCT1 is important for neuronal energy homeostasis in the aging central nervous system (CNS). The reduction in OL MCT1 that occurs with aging may enhance the risk for axonal degeneration and atrophy in neurodegenerative diseases. [Display omitted] •Lack of MCT1-mediated oligodendrocyte metabolic support is well tolerated early on•Loss of oligodendrocyte MCT1-driven metabolic support causes axonal degeneration•Loss of oligodendrocyte MCT1-mediated metabolic support causes axonal hypomyelination Using conditional cell-specific deletion of MCT1, Philips et al. learn that oligodendrocyte lineage cells are actually dispensable for normal myelination and axonal energy homeostasis during early life but that the oligodendroglial lactate/MCT1-based support is critical for the aging of the nervous system.