title: Alpha-Ketoglutarate Curbs Differentiation and Induces Cell Death in Mesenchymal Stromal Precursors with Mitochondrial Dysfunction.
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.
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Karmveer
authors.identifier: 0000-0002-1237-7417
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Krug
authors.affiliation: Department of Dermatology and Allergic Diseases.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Meyer
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Treiber
authors.affiliation: Department of Dermatology and Allergic Diseases.
authors.forename: Seppe
authors.initials: S
authors.lastname: Vander Beken
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.affiliation: Department of Gene Therapy.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.affiliation: German Sport University Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.|Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Ulm, Germany.|Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Pallab
authors.initials: P
authors.lastname: Maity
authors.affiliation: Department of Dermatology and Allergic Diseases.|Aging Research Center (ARC), Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005973:Glutamine / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D019289:Pyruvic Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D002843:Chromatin; D005973:Glutamine; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D019289:Pyruvic Acid; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C497443:Hif1a protein, mouse
keywords: Aging; Differentiation; Epigenetics; Hypoxia; Mesenchymal stem cells; Multipotential differentiation; Osteoporosis; Plasticity