High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation.
High glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation.
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DOI：
10.1042/bj20141018
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Jones SP
中科院分区：
文献类型：
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作者：
Dassanayaka S;Readnower RD;Salabei JK;Long BW;Aird AL;Zheng YT;Muthusamy S;Facundo HT;Hill BG;Jones SP
糖尿病的特征是高血糖和中间代谢紊乱。特别是，糖尿病可以增加通过葡萄糖代谢的辅助途径的通量，例如己糖胺生物合成途径（HBP），其产生用于蛋白质的β-O-连接的-N-乙酰葡糖胺（O-GlcNAc）翻译后修饰的糖供体。糖尿病也促进线粒体功能障碍。然而，糖尿病、高脂血症、线粒体功能障碍和O-GlcNAc修饰之间的关系仍不清楚。在本研究中，我们测试了高诱导的O-GlcNAc修饰的增加是否直接调节分离的心肌细胞中的线粒体功能。高浓度葡萄糖（33 mM）增加O-GlcNAc酰化与心肌细胞基础和最大呼吸减少、线粒体储备能力降低和复合物II依赖性呼吸降低相关（P < 0.05）;然而，在正常或高葡萄糖条件下O-GlcNAc修饰的药理学或遗传学调节显示对线粒体呼吸几乎没有显著影响，提示O-GlcNAc在调节心肌细胞线粒体功能中不起主要作用。此外，渗透压控制重现了高糖诱导的线粒体代谢变化（P < 0.05），而没有增加O-GlcNAc化。因此，在分离的心肌细胞中，增加的O-GlcNAc酰化对于高葡萄糖诱导的线粒体代谢抑制既不充分也不必要。
Diabetes is characterized by hyperglycaemia and perturbations in intermediary metabolism. In particular, diabetes can augment flux through accessory pathways of glucose metabolism, such as the hexosamine biosynthetic pathway (HBP), which produces the sugar donor for the β-O-linked-N-acetylglucosamine (O-GlcNAc) post-translational modification of proteins. Diabetes also promotes mitochondrial dysfunction. Nevertheless, the relationships among diabetes, hyperglycaemia, mitochondrial dysfunction and O-GlcNAc modifications remain unclear. In the present study, we tested whether high-induced increases in O-GlcNAc modifications directly regulate mitochondrial function in isolated cardiomyocytes. Augmentation of O-GlcNAcylation with high glucose (33 mM) was associated with diminished basal and maximal cardiomyocyte respiration, a decreased mitochondrial reserve capacity and lower Complex II-dependent respiration (P < 0.05); however, pharmacological or genetic modulation of O-GlcNAc modifications under normal or high glucose conditions showed few significant effects on mitochondrial respiration, suggesting that O-GlcNAc does not play a major role in regulating cardiomyocyte mitochondrial function. Furthermore, an osmotic control recapitulated high-glucose-induced changes to mitochondrial metabolism (P < 0.05) without increasing O-GlcNAcylation. Thus, increased O-GlcNAcylation is neither sufficient nor necessary for high-glucose-induced suppression of mitochondrial metabolism in isolated cardiomyocytes.