Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function

Nina-Lydia Kazakou, Nadine Bestard-Cuche, Laura J. Wagstaff, Kellie Horan, Luise Seeker, Sunniva Bøstrand, Rana Fetit, Rebecca Sherrard Smith, Fabio Baldivia Pohl, Bjorn Neumann, Patrick Keeler, Robin J. M. Franklin and Anna Williams ()
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Nina-Lydia Kazakou: University of Edinburgh
Nadine Bestard-Cuche: University of Edinburgh
Laura J. Wagstaff: University of Edinburgh
Kellie Horan: University of Edinburgh
Luise Seeker: University of Edinburgh
Sunniva Bøstrand: University of Edinburgh
Rana Fetit: University of Edinburgh
Rebecca Sherrard Smith: University of Edinburgh
Fabio Baldivia Pohl: Karolinska Institutet
Bjorn Neumann: University of Cambridge
Patrick Keeler: RWTH Aachen University
Robin J. M. Franklin: University of Cambridge
Anna Williams: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Metformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin’s brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection.

Date: 2025
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DOI: 10.1038/s41467-025-63279-4

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