Alpha‐Ketoglutarate Curbs Differentiation and Induces Cell Death in Mesenchymal Stromal Precursors with Mitochondrial Dysfunction. (2nd May 2017)

• Record Type: Journal Article
• Authors: Singh, Karmveer; Krug, Linda; Basu, Abhijit; Meyer, Patrick; Treiber, Nicolai; Vander Beken, Seppe; Wlaschek, Meinhard; Kochanek, Stefan; Bloch, Wilhelm; Geiger, Hartmut; Maity, Pallab; Scharffetter‐Kochanek, Karin
• Is Part Of: Stem cells. Volume 35:Number 7(2017:Jul.)
• Page Start: 1704
• Page End: 1718
• Publication Date: 2017-05-02
• Subjects: Aging -- Differentiation -- Epigenetics -- Mesenchymal stem cells -- Multipotential differentiation -- Osteoporosis -- Plasticity -- Hypoxia; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2629
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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 andl ‐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. Stem Cells 2017;35:1704–1718 Abstract : Graphics summary illustrating distinct molecular interventions that AKG employ to induce nucleocytoplasmic vacuolation, chromatin condensation and subsequent differentiation defects as well as cell death in Sod2 deficient stromal precursors.