Cell-autonomous mitochondrial calcium flux governs oligodendrocyte regeneration

Oligodendrocyte (OL) lineage cells drive central nervous system remyelination, yet the intrinsic mechanisms that define their regenerative potential remain unclear. We identify spontaneous, cell-autonomous intracellular Ca ²⁺ signaling as a critical mechanism regulating OL regeneration following demyelination. Longitudinal in vivo imaging and ex vivo recordings reveal that Ca ²⁺ signaling arises intrinsically within OL lineage cells after demyelination, and occurs independently from neuronal or behavioral activity. Mechanistically, mitochondrial Ca ²⁺ flux sustains intracellular Ca ²⁺ signals in oligodendroglia, and its in vivo disruption impairs oligodendrocyte precursor cell (OPC) proliferation, differentiation, and repopulation at the lesion site. Conversely, enhancing oligodendroglial Ca ²⁺ signaling in vivo using chemogenetics stimulates lineage expansion and differentiation. In primary human OPC cultures, modulation of mitochondrial Ca ²⁺ flux similarly reduces proliferation, indicating a conserved role for this pathway across species. These findings identify mitochondrial Ca ²⁺ flux as a central driver of the oligodendroglial regeneration and a potential therapeutic target in demyelinating diseases.