Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells

Fernandez Guerra, P.; Kjaer, P. K.; Terp, S. K.; Thomsen, J. S.; Aldana, B.; Renkema, H.; Smeitink, J.; Andersen, P. H.; Palmfeldt, J.; Soe, K.; Andersen, T. L.; Kassem, M.; Frost, M.; Frekeriksen, A.

doi:10.1101/2024.12.24.629993

bioRxiv · 10.1101/2024.12.24.629993

Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells

Fernandez Guerra, P.·Kjaer, P. K.·Terp, S. K.·Thomsen, J. S.·Aldana, B.·Renkema, H.·Smeitink, J.·Andersen, P. H.·Palmfeldt, J.·Soe, K.·Andersen, T. L.·Kassem, M.·Frost, M.·Frekeriksen, A.

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Abstract

Bone formation is critical to maintain bone integrity. Here, we studied the importance of intact energy metabolism for bone formation in humans. The skeletal impact of impaired oxidative phosphorylation (OXPHOS) was investigated in adult individuals with genetically defective mitochondrial DNA translation (m.3243A>G). Although impaired mitochondrial ATP production in m.3243A>G human bone marrow stromal cells (hBMSC) was compensated by increased glycolytic ATP production (unchanged net ATP production), both in vitro osteoblast differentiation and in vivo ectopic bone formation were decreased. The impaired OXPHOS was associated with mitochondrial stress and disruption of the pro-osteogenic transcriptional program characteristic of hBMSC. Supporting OXPHOS pharmacologically in hBMSC restored mitochondrial ATP production, their transcriptional program and metabolism, leading to upregulation of osteogenic genes and restoration of bone formation capacity. These findings demonstrate a mitochondrial regulation mechanism of the osteogenic capacity of hBMSCs and identify OXPHOS as a potential target for increasing bone formation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/629993v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@fca817org.highwire.dtl.DTLVardef@17fb2d3org.highwire.dtl.DTLVardef@b5667forg.highwire.dtl.DTLVardef@15c35db_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Fernandez Guerra, P., Kjaer, P. K., Terp, S. K., Thomsen, J. S., Aldana, B., Renkema, H., Smeitink, J., Andersen, P. H., Palmfeldt, J., Soe, K., Andersen, T. L., Kassem, M., Frost, M., Frekeriksen, A.. 2024-12-24. Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells. https://doi.org/10.1101/2024.12.24.629993

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