Journal
STEM CELLS
Volume 35, Issue 7, Pages 1704-1718Publisher
WILEY
DOI: 10.1002/stem.2629
Keywords
Aging; Differentiation; Epigenetics; Mesenchymal stem cells; Multipotential differentiation; Osteoporosis; Plasticity; Hypoxia
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Funding
- German Research Foundation (DFG) within the Clinical Research Group KFO142 [SCHA411/15-2]
- Graduate Training Centre [GRK 1789]
- Collaborative Research Center 1149 for trauma research at Ulm
- Forderlinie Perspektivforderung Zellulare Entscheidungs- und Signalwege bei der Alterung of the Ministerium fur Wissenschaft, Forschung und Kunst Baden-Wurttemberg, Germany
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Increased concentrations of reactive oxygen species (ROS) originating from dysfunctional mitochondria contribute to diverse aging-related degenerative disorders. But so far little is known about the impact of distinct ROS on metabolism and fate of stromal precursor cells. Here, we demonstrate that an increase in superoxide anion radicals due to superoxide dismutase 2 (Sod2) deficiency in stromal precursor cells suppress osteogenic and adipogenic differentiation through fundamental changes in the global metabolite landscape. Our data identify impairment of the pyruvate and 1-glutamine metabolism causing toxic accumulation of alpha-ketoglutarate in the Sod2-deficient and intrinsically aged stromal precursor cells as a major cause for their reduced lineage differentiation. Alpha-ketoglutarate accumulation led to enhanced nucleocytoplasmic vacuolation and chromatin condensation-mediated cell death in Sod2-deficient stromal precursor cells as a consequence of DNA damage, Hif-17 instability, and reduced histone H3 (Lys27) acetylation. These findings hold promise for prevention and treatment of mitochondrial disorders commonly associated with aged individuals.
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