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Oligodendrocyte-encoded Lactate Dehydrogenase A Couples Glycolysis to (Re)myelination via Protein Lactylation-2

ABSTRACT: Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production, in contrast to the mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of Lactate Dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1+ OLs, significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1+ lineage or CNPase+ premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that oligodendrocytes within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couple glycolysis with oligodendrocyte maturation. Our findings elucidate the metabolic interplay between glycolysis, lactylation, and oligodendrocyte maturation, and provide novel enzymatic therapeutic perspectives for demyelinating disorders for which effective therapies are currently lacking.

ORGANISM(S): Mus Musculus

SUBMITTER: Yuan Zhang

PROVIDER: PXD075375 | iProX | Fri Mar 06 00:00:00 GMT 2026

REPOSITORIES: iProX

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