PDF(Pubmed)
Abstract：
Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate-keeping enzyme for mitochondrial glucose oxidation. In this study, a small-molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and 13 C-metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK-PDC-mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK-N-SH cells validated that SG could rescue mitochondrial damage via the PDK-PDC axis, promote the MMP level and reduce the mitochondria-dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK-PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK-PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.
摘要：
线粒体生物能量缺陷及其导致的葡萄糖低代谢是促进神经变性的关键病理生理调节剂。然而,目前还没有发现通过调节能量代谢和修复线粒体损伤来治疗神经系统疾病的特定潜在分子。丙酮酸脱氢酶（PDH）复合物（PDC），它可以被丙酮酸脱氢酶激酶（PDK）磷酸化，是线粒体葡萄糖氧化的大门保持酶。在这项研究中,发现小分子灯盏乙素(SG)能明显减轻脑低灌注模型大鼠海马CA1区的神经病理学改变,拯救了异常线粒体的形态变化，恢复了线粒体稳态.线粒体蛋白质组学,能量代谢监测，和13C-代谢通量分析靶向PDK2上的SG活性,从而在线粒体OXPHOS损伤期间调节PDK-PDC介导的糖酵解代谢至TCA循环。SK-N-SH细胞中PDK2的敲减证实SG可以通过PDK-PDC轴挽救线粒体损伤,促进MMP水平，减少线粒体依赖性凋亡。总的来说，这项研究探索了新的治疗方法：PDK-PDC轴用于神经损伤和认知障碍，并揭示了SG通过PDK-PDC轴和线粒体葡萄糖氧化对线粒体保护的影响。研究结果表明，改善线粒体生物能缺陷的活性成分可能对神经系统疾病的治疗具有重要价值。
