Related Experiment Video
Updated: Aug 7, 2026
MitoCeption: Transferring Isolated Human MSC Mitochondria to Glioblastoma Stem Cells
Published on: February 22, 2017
Alpha-Ketoglutarate Curbs Differentiation and Induces Cell Death in Mesenchymal Stromal Precursors with Mitochondrial
Karmveer Singh1,2, Linda Krug1,2, Abhijit Basu1
1Department of Dermatology and Allergic Diseases.
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 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. Stem Cells 2017;35:1704-1718.
Insights
Superoxide dismutase 2 (Sod2) deficiency in stromal cells impairs differentiation by altering metabolism. Toxic alpha-ketoglutarate accumulation causes cell death, impacting aging and mitochondrial disorders.
Area of Science:
- Mitochondrial biology
- Cellular metabolism
- Stem cell differentiation
Background:
- Mitochondrial dysfunction and reactive oxygen species (ROS) are implicated in aging.
- The specific roles of ROS in stromal precursor cell metabolism and differentiation remain unclear.
Purpose of the Study:
- To investigate the impact of superoxide anion radicals on stromal precursor cell differentiation and metabolism.
- To identify the underlying molecular mechanisms linking ROS to impaired cell fate.
Main Methods:
- Utilized superoxide dismutase 2 (Sod2)-deficient stromal precursor cells.
- Analyzed global metabolite profiles and lineage differentiation (osteogenic and adipogenic).
- Investigated mechanisms of cell death, including DNA damage and histone acetylation.
Main Results:
- Sod2 deficiency led to increased superoxide radicals, suppressing osteogenic and adipogenic differentiation.
- Impaired pyruvate and L-glutamine metabolism caused toxic alpha-ketoglutarate accumulation.
- Alpha-ketoglutarate accumulation induced cell death via DNA damage, Hif-1α instability, and reduced histone acetylation.
Conclusions:
- Impaired mitochondrial metabolism, specifically alpha-ketoglutarate accumulation due to Sod2 deficiency, drives stromal precursor cell dysfunction.
- These findings offer insights into aging-related degenerative disorders and mitochondrial diseases.
- Targeting these metabolic pathways may provide therapeutic strategies for age-related conditions.
More Related Videos
10:28Flow Cytometry-based Drug Screening System for the Identification of Small Molecules That Promote Cellular Differentiation of Glioblastoma Stem Cells
Published on: January 10, 2018
06:24Comparison of Two Representative Methods for Differentiation of Human Induced Pluripotent Stem Cells into Mesenchymal Stromal Cells
Published on: October 20, 2023
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:19Mesenchymal Stem Cells