Alpha-Ketoglutarate Curbs Differentiation and Induces Cell Death in Mesenchymal Stromal Precursors with Mitochondrial Dysfunction
| Autor: | Karin Scharffetter-Kochanek, Wilhelm Bloch, Karmveer Singh, Abhijit Basu, Stefan Kochanek, Patrick Meyer, Nicolai Treiber, Pallab Maity, Hartmut Geiger, Meinhard Wlaschek, Seppe Vander Beken, Linda Krug |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Aging Stromal cell Glutamine Primary Cell Culture SOD2 Histones Superoxide dismutase Mice 03 medical and health sciences chemistry.chemical_compound Chondrocytes Alpha ketoglutarate Precursor cell Pyruvic Acid Adipocytes Animals Skin Mice Knockout chemistry.chemical_classification Reactive oxygen species Osteoblasts Cell Death biology Superoxide Dismutase Superoxide Mesenchymal stem cell Cell Differentiation Mesenchymal Stem Cells Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Chromatin Mitochondria Cell biology 030104 developmental biology Animals Newborn Gene Expression Regulation chemistry Metabolome biology.protein Ketoglutaric Acids Molecular Medicine Reactive Oxygen Species Developmental Biology |
| Zdroj: | Stem Cells. 35:1704-1718 |
| ISSN: | 1549-4918 1066-5099 |
| DOI: | 10.1002/stem.2629 |
| Popis: | 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 l-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-1α instability, and reduced histone H3 (Lys27) acetylation. These findings hold promise for prevention and treatment of mitochondrial disorders commonly associated with aged individuals. |
| Databáze: | OpenAIRE |
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