Cell-autonomous mitochondrial calcium flux governs oligodendrocyte regeneration
Maas, D. A.; Bancel-Vega, R.; Baudouin, L. R.; Bun, P.; Manot-Saillet, B.; Habermacher, C.; Verburg, N.; Rusconi, F.; Angulo, M. C.
Show abstract
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 Ca2+ signaling as a critical mechanism regulating OL regeneration following demyelination. Longitudinal in vivo imaging and ex vivo recordings reveal that Ca2+ signaling arises intrinsically within OL lineage cells after demyelination, and occurs independently from neuronal or behavioral activity. Mechanistically, mitochondrial Ca2+ flux sustains intracellular Ca2+ signals in oligodendroglia, and its in vivo disruption impairs oligodendrocyte precursor cell (OPC) proliferation, differentiation, and repopulation at the lesion site. Conversely, enhancing oligodendroglial Ca2+ signaling in vivo using chemogenetics stimulates lineage expansion and differentiation. In primary human OPC cultures, modulation of mitochondrial Ca2+ flux similarly reduces proliferation, indicating a conserved role for this pathway across species. These findings identify mitochondrial Ca2+ flux as a central driver of the oligodendroglial regeneration and a potential therapeutic target in demyelinating diseases.
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