文章：

线粒体O-GlcNAc转移酶（mOGT）上调介导的O-GlcNAc糖基化增强通过抑制呼吸链复合物活性调控细胞生物能量代谢

Increased O-GlcNAcylation by Upregulation of Mitochondrial O-GlcNAc Transferase (mOGT) Inhibits the Activity of Respiratory Chain Complexes and Controls Cellular Bioenergetics

原文发布日期：5 March 2024

DOI: 10.3390/cancers16051048

类型: Article

开放获取: 是

英文摘要：

O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible post-translational modification involved in the regulation of cytosolic, nuclear, and mitochondrial proteins. The interplay between O-GlcNAcylation and phosphorylation is critical to control signaling pathways and maintain cellular homeostasis. The addition of O-GlcNAc moieties to target proteins is catalyzed by O-linked N-acetylglucosamine transferase (OGT). Of the three splice variants of OGT described, one is destined for the mitochondria (mOGT). Although the effects of O-GlcNAcylation on the biology of normal and cancer cells are well documented, the role of mOGT remains poorly understood. In this manuscript, the effects of mOGT on mitochondrial protein phosphorylation, electron transport chain (ETC) complex activity, and the expression of VDAC porins were investigated. We performed studies using normal and breast cancer cells with upregulated mOGT or its catalytically inactive mutant. Proteomic approaches included the isolation of O-GlcNAc-modified proteins of the electron transport chain, followed by their analysis using mass spectrometry. We found that mitochondrial OGT regulates the activity of complexes I-V of the respiratory chain and identified a group of 19 ETC components as mOGT substrates in mammary cells. Furthermore, we observed that the upregulation of mOGT inhibited the interaction of VDAC1 with hexokinase II. Our results suggest that the deregulation of mOGT reprograms cellular energy metabolism via interaction with and O-GlcNAcylation of proteins involved in ATP production in mitochondria and its exchange between mitochondria and the cytosol.

摘要翻译： 

O-连接β-N-乙酰葡糖胺（O-GlcNAc）是一种可逆的翻译后修饰，参与调控细胞质、细胞核及线粒体蛋白的功能。O-GlcNAc修饰与磷酸化之间的相互作用对调控信号通路和维持细胞稳态至关重要。靶蛋白的O-GlcNAc修饰由O-连接N-乙酰葡糖胺转移酶（OGT）催化。在已报道的三种OGT剪接变体中，其中一种定位于线粒体（mOGT）。尽管O-GlcNAc修饰对正常细胞和癌细胞生物学功能的影响已有充分记载，但mOGT的具体作用机制仍不明确。本研究探讨了mOGT对线粒体蛋白磷酸化、电子传递链（ETC）复合体活性以及VDAC孔蛋白表达的影响。我们通过上调正常细胞和乳腺癌细胞中的mOGT或其催化失活突变体进行实验分析。蛋白质组学方法包括分离电子传递链中O-GlcNAc修饰的蛋白，并采用质谱技术进行鉴定。研究发现线粒体OGT能调控呼吸链复合体I-V的活性，并在乳腺细胞中鉴定出19种电子传递链组分作为mOGT的作用底物。此外，我们观察到mOGT的上调会抑制VDAC1与己糖激酶II的相互作用。这些结果表明，mOGT的失调可通过与线粒体内ATP生成相关蛋白及其在线粒体与细胞质间交换过程的相互作用和O-GlcNAc修饰，实现对细胞能量代谢的重编程。

原文链接：

Increased O-GlcNAcylation by Upregulation of Mitochondrial O-GlcNAc Transferase (mOGT) Inhibits the Activity of Respiratory Chain Complexes and Controls Cellular Bioenergetics