Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Cell Stress Chaperones. 2022 Sep;27(5):573-585. doi: 10.1007/s12192-022-01293-x. Epub 2022 Aug 17.
The molecular chaperone TNF-receptor-associated protein-1 (TRAP1) controls mitochondrial respiration through regulation of Krebs cycle and electron transport chain activity. Post-translational modification (PTM) of TRAP1 regulates its activity, thereby controlling global metabolic flux. O-GlcNAcylation is one PTM that is known to impact mitochondrial metabolism, however the major effectors of this regulatory PTM remain inadequately resolved. Here we demonstrate that TRAP1-O-GlcNAcylation decreases TRAP1 ATPase activity, leading to increased mitochondrial metabolism. O-GlcNAcylation of TRAP1 occurs following mitochondrial import and provides critical regulatory feedback, as the impact of O-GlcNAcylation on mitochondrial metabolism shows TRAP1-dependence. Mechanistically, loss of TRAP1-O-GlcNAcylation decreased TRAP1 binding to ATP, and interaction with its client protein succinate dehydrogenase (SDHB). Taken together, TRAP1-O-GlcNAcylation serves to regulate mitochondrial metabolism by the reversible attenuation of TRAP1 chaperone activity.
分子伴侣 TNF 受体相关蛋白-1（TRAP1）通过调节克雷布斯循环和电子传递链活性来控制线粒体呼吸。TRAP1 的翻译后修饰（PTM）调节其活性，从而控制整体代谢通量。O-GlcNAc 化是已知影响线粒体代谢的一种 PTM，但这种调节 PTM 的主要效应物仍未得到充分解决。在这里，我们证明 TRAP1-O-GlcNAc 化降低了 TRAP1 的 ATP 酶活性，导致线粒体代谢增加。TRAP1 的 O-GlcNAc 化发生在线粒体导入之后，并提供关键的调节反馈，因为 O-GlcNAc 化对线粒体代谢的影响显示出 TRAP1 的依赖性。从机制上讲，失去 TRAP1-O-GlcNAc 化会降低 TRAP1 与 ATP 的结合，并与它的客户蛋白琥珀酸脱氢酶（SDHB）相互作用。总之，TRAP1-O-GlcNAc 化通过可逆衰减 TRAP1 伴侣活性来调节线粒体代谢。
