O-GlcNAcylation 通过线粒体、细胞骨架和内质网的形态变化调控成骨细胞分化。

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY BioFactors Pub Date : 2024-10-15 DOI:10.1002/biof.2131
Yao Weng, Ziyi Wang, Heriati Sitosari, Mitsuaki Ono, Hirohiko Okamura, Toshitaka Oohashi
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引用次数: 0

摘要

为了探索O-连锁-N-乙酰葡萄糖氨酰化(O-GlcNAcylation)调控成骨过程的潜在机制,我们通过文献挖掘对公开的RNA-seq数据集进行了重新分析,结果显示O-GlcNAcylation在成骨细胞中的主要靶标是线粒体/骨架。尽管O-GlcNAcylation调控的线粒体/细胞骨架已被广泛研究,但其在成骨过程中的具体作用仍不清楚。为了解决这个问题,我们敲除了 MC3T3-E1 成骨细胞中的 Ogt(Ogt-KO)。结果发现,Ogt-KO 细胞的成骨细胞分化、运动、增殖、线粒体-内质网(Mito-ER)耦合、ER 容量、核小管蛋白和氧代谢均明显降低。通过人工智能(AI)预测的细胞结构,活细胞延时成像与活性氧物种/缺氧染色显示,Ogt-KO细胞中较低的细胞增殖和氧代谢改变与Mito-ER耦合相关。生物信息学分析结合相关的mRNA和蛋白质表达表明,Ezh2及其下游靶标(Opa1、Gsk3a、Wnt3a、Hif1a和Hspa9)可能参与了O-GlcNAcylation调控的Mito-ER偶联,最终影响成骨细胞的分化。总之,我们的研究结果表明,O-GlcNAcylation调控的成骨细胞分化与线粒体、细胞骨架和ER的形态变化有关,而Ezh2可能起着关键作用。
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O-GlcNAcylation regulates osteoblast differentiation through the morphological changes in mitochondria, cytoskeleton, and endoplasmic reticulum.

To explore the potential mechanisms which O-linked-N-acetylglucosaminylation (O-GlcNAcylation) regulates osteogenesis, a publicly RNA-seq dataset was re-analyzed with literature-mining and showed the primary targets of O-GlcNAcylation in osteoblasts are mitochondria/cytoskeleton. Although the O-GlcNAcylation-regulated mitochondria/cytoskeleton has been extensively studied, its specific role during osteogenesis remains unclear. To address this, we knocked out Ogt (Ogt-KO) in MC3T3-E1 osteoblastic cells. Then, significantly reduced osteoblast differentiation, motility, proliferation, mitochondria-endoplasmic reticulum (Mito-ER) coupling, volume of ER, nuclear tubulins, and oxygen metabolism were observed in Ogt-KO cells. Through artificial intelligence (AI)-predicted cellular structures, the time-lapse live cells imaging with reactive-oxygen-species/hypoxia staining showed that lower cell proliferation and altered oxygen metabolism in the Ogt-KO cells were correlated with the Mito-ER coupling. Bioinformatics analysis, combined with correlated mRNA and protein expression, suggested that Ezh2 and its downstream targets (Opa1, Gsk3a, Wnt3a, Hif1a, and Hspa9) may be involved in O-GlcNAcylation-regulated Mito-ER coupling, ultimately impacting osteoblast differentiation. In conclusion, our findings indicate that O-GlcNAcylation-regulated osteoblast differentiation is linked to morphological changes in mitochondria, cytoskeleton, and ER, with Ezh2 potentially playing a crucial role.

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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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