Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China.
Cell Death Differ. 2018 Feb;25(2):229-240. doi: 10.1038/cdd.2017.144. Epub 2017 Sep 15.
Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by increased ATP production and decreased mitochondrial stress. Inhibition of mitochondrial activity or an increase in mitochondrial superoxide production significantly suppressed osteoblast differentiation. During differentiation, SOD2 was specifically induced to eliminate excess mitochondrial superoxide and protein oxidation, whereas SIRT3 expression was increased to enhance SOD2 activity through deacetylation of K68. Both SOD2 and SIRT3 knockdown resulted in suppression of differentiation. Meanwhile, mice deficient in SIRT3 exhibited obvious osteopenia accompanied by osteoblast dysfunction, whereas overexpression of SOD2 or SIRT3 improved the differentiation capability of primary osteoblasts derived from SIRT3-deficient mice. These results suggest that SIRT3/SOD2 is required for regulating mitochondrial stress and plays a vital role in osteoblast differentiation and bone formation.
最近的研究揭示了细胞分化过程中强大的代谢变化。线粒体是许多重要代谢反应发生的细胞器，可能起着重要的作用。在这里，我们报告了 SIRT3 调节的线粒体应激在成骨细胞分化和骨形成中的参与。在成骨细胞系 MC3T3-E1 和原代颅骨成骨细胞中，分化过程中观察到强大的线粒体生物发生和超复合体形成，伴随着 ATP 产生增加和线粒体应激减少。线粒体活性的抑制或线粒体超氧化物产生的增加显著抑制成骨细胞分化。在分化过程中，SOD2 被特异性诱导以消除多余的线粒体超氧化物和蛋白质氧化，而 SIRT3 的表达增加通过 K68 的去乙酰化来增强 SOD2 的活性。SOD2 和 SIRT3 的敲低都导致分化受到抑制。同时，SIRT3 缺陷的小鼠表现出明显的骨质疏松症，伴有成骨细胞功能障碍，而过表达 SOD2 或 SIRT3 可改善源自 SIRT3 缺陷小鼠的原代成骨细胞的分化能力。这些结果表明，SIRT3/SOD2 是调节线粒体应激所必需的，在成骨细胞分化和骨形成中起着至关重要的作用。
Zotero 插件
