Hypoxia promotes osteogenesis by facilitating acetyl‐CoA‐mediated mitochondrial–nuclear communication
Open Access
- 24 October 2022
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 41 (23), e111239
- https://doi.org/10.15252/embj.2022111239
Abstract
Bone-derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial-nuclear communication during stem cell differentiation. We show that normoxia-cultured murine MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces metabolic rewiring resulting in elevated acetyl-CoA levels, histone hypo-acetylation occurs due to the trapping of acetyl-CoA inside mitochondria owing to decreased citrate carrier (CiC) activity. Restoring the cytosolic acetyl-CoA pool remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is perturbed upon exposure to high oxygen levels and identifies CiC as a novel, oxygen-sensitive regulator of the MSC function.Keywords
Funding Information
- Alexander von Humboldt-Stiftung
- Cancer Research UK (C51061/A27453)
- Max-Planck-Gesellschaft
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