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bioRxiv · 10.1101/2025.11.18.689087

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.
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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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Maas, D. A., Bancel-Vega, R., Baudouin, L. R., Bun, P., Manot-Saillet, B., Habermacher, C., Verburg, N., Rusconi, F., Angulo, M. C.. 2025-11-18. Cell-autonomous mitochondrial calcium flux governs oligodendrocyte regeneration. https://doi.org/10.1101/2025.11.18.689087

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