Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes
Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes
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DOI：
10.1074/jbc.m112.390682
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发表时间：
2012-08-24
影响因子：
4.8
通讯作者：
Dillmann, Wolfgang
中科院分区：
文献类型：
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作者：
Gawlowski, Thomas;Suarez, Jorge;Dillmann, Wolfgang
细胞蛋白质的丝氨酸和苏氨酸残基的O-连接-N-乙酰基-葡糖胺糖基化（O-GlcNAc化）是一个动态过程并影响磷酸化。延长的O-GlcNAc化与糖尿病相关并发症有关，包括线粒体功能障碍。线粒体是动态重塑的细胞器，不断融合（融合）和分裂（裂变）。这个过程的不平衡会影响线粒体功能。在这项研究中，我们发现，动力蛋白相关蛋白1（DRP 1）是O-GlcNAc酰化的心肌细胞在苏氨酸585和586。通过N-乙酰氨基葡萄糖苷酶的化学抑制，O-GlcNAc化显著增强。增加的O-GlcNAc酰化降低了DRP 1在丝氨酸637处的磷酸化，已知其调节DRP 1功能。事实上，增加的O-GlcNAc化增加了GTP结合的活性形式的DRP 1的水平，并诱导DRP 1从细胞质易位到线粒体。线粒体断裂和线粒体膜电位降低也伴随着O-GlcNAc化的增加。总之，本报告首次表明，O-GlcNAc酰化调节心肌细胞中的DRP 1功能。
O-linked-N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of the serine and threonine residues of cellular proteins is a dynamic process and affects phosphorylation. Prolonged O-GlcNAcylation has been linked to diabetes-related complications, including mitochondrial dysfunction. Mitochondria are dynamically remodeling organelles, that constantly fuse (fusion) and divide (fission). An imbalance of this process affects mitochondrial function. In this study, we found that dynamin-related protein 1 (DRP1) is O-GlcNAcylated in cardiomyocytes at threonine 585 and 586. O-GlcNAcylation was significantly enhanced by the chemical inhibition of N-acetyl-glucosaminidase. Increased O-GlcNAcylation decreases the phosphorylation of DRP1 at serine 637, which is known to regulate DRP1 function. In fact, increased O-GlcNAcylation augments the level of the GTP-bound active form of DRP1 and induces translocation of DRP1 from the cytoplasm to mitochondria. Mitochondrial fragmentation and decreased mitochondrial membrane potential also accompany the increased O-GlcNAcylation. In conclusion, this report shows, for the first time, that O-GlcNAcylation modulates DRP1 functionality in cardiac muscle cells.