Department of Dermatology and Allergic Diseases.
Aging Research Center (ARC), Ulm, Germany.
Stem Cells. 2017 Jul;35(7):1704-1718. doi: 10.1002/stem.2629. Epub 2017 May 2.
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.
功能失调的线粒体产生的活性氧（ROS）浓度增加会导致多种与衰老相关的退行性疾病。但到目前为止，人们对不同 ROS 对基质前体细胞代谢和命运的影响知之甚少。在这里，我们证明由于基质前体细胞中的超氧化物歧化酶 2（Sod2）缺乏导致超氧阴离子自由基增加，通过全局代谢物图谱的根本变化，抑制成骨和脂肪生成分化。我们的数据确定了丙酮酸和 l-谷氨酰胺代谢的损伤，导致 α-酮戊二酸在 Sod2 缺乏和内在老化的基质前体细胞中的毒性积累，这是它们减少谱系分化的主要原因。由于 DNA 损伤、Hif-1α 不稳定性和组蛋白 H3（Lys27）乙酰化减少，α-酮戊二酸的积累导致 Sod2 缺乏的基质前体细胞中核质空泡化和染色质浓缩介导的细胞死亡。这些发现为预防和治疗与老年人常见的线粒体疾病提供了希望。干细胞 2017;35:1704-1718。
