Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Biodesign Institute, The School of Molecular Sciences, Arizona State University, Tempe, AZ, USA.
Nat Metab. 2024 Sep;6(9):1712-1735. doi: 10.1038/s42255-024-01121-9. Epub 2024 Sep 11.
Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.
葡萄糖是细胞的主要能量来源，通过限速酶己糖激酶（HK）启动的糖酵解进行代谢。在大脑等能量需求高的组织中，HK1 是主要的同工酶，主要定位于线粒体，对于高效的糖酵解-氧化磷酸化偶联和最佳能量产生至关重要。这项研究揭示了一种由代谢传感器酶 O-连接的 N-乙酰葡萄糖胺转移酶（OGT）介导的调节 HK1 活性、糖酵解和线粒体偶联动力学的独特机制。OGT 催化可逆的 O-连接的 N-乙酰葡萄糖胺化，这是一种受葡萄糖通量影响的翻译后修饰。OGT 活性的升高诱导 HK1 调节结构域的动态 O-连接的 N-乙酰葡萄糖胺化，随后促进糖酵解代谢物在外膜上的组装。这种修饰增强了 HK1 与线粒体的关联，协调糖酵解和线粒体 ATP 的产生。HK1 的 O-连接的 N-乙酰葡萄糖胺化位点的突变会降低多种细胞类型中的 ATP 生成，特别是影响神经元中的代谢效率。这项研究揭示了一条以前未被认识的途径，通过 OGT 和糖酵解代谢物的形成将神经元代谢和线粒体功能联系起来，为解决代谢和神经紊乱提供了潜在策略。
