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Scutellarin Rescued Mitochondrial Damage through Ameliorating Mitochondrial Glucose Oxidation via the Pdk-Pdc Axis
Advanced Science ( IF 14.3 ) Pub Date : 2023-09-26 , DOI: 10.1002/advs.202303584 Ning Sheng 1 , Zhihui Zhang 1 , Hao Zheng 1 , Congyu Ma 1 , Menglin Li 1 , Zhe Wang 1 , Lulu Wang 2 , Jiandong Jiang 1, 2 , Jinlan Zhang 1
Advanced Science ( IF 14.3 ) Pub Date : 2023-09-26 , DOI: 10.1002/advs.202303584 Ning Sheng 1 , Zhihui Zhang 1 , Hao Zheng 1 , Congyu Ma 1 , Menglin Li 1 , Zhe Wang 1 , Lulu Wang 2 , Jiandong Jiang 1, 2 , Jinlan Zhang 1
Affiliation
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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 13C-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.
中文翻译：
灯盏乙素通过 Pdk-Pdc 轴改善线粒体葡萄糖氧化来挽救线粒体损伤
线粒体生物能缺陷及其导致的葡萄糖代谢低下是促进神经退行性变的关键病理生理调节因子。然而，目前还没有发现特定的潜在分子可以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。丙酮酸脱氢酶 (PDH) 复合物 (PDC) 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看门酶。本研究发现一种小分子灯盏花乙素（SG）能够显着缓解脑低灌注模型大鼠海马CA1区的神经病理改变，挽救异常线粒体的形态变化，恢复线粒体稳态。线粒体蛋白质组学、能量代谢监测和13 C 代谢流分析以 PDK2 上的 SG 活性为目标，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的敲低证实SG可以通过PDK-PDC轴挽救线粒体损伤，促进MMP水平并减少线粒体依赖性细胞凋亡。总的来说，本研究探索了新的治疗方法：PDK-PDC 轴治疗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治疗具有重要价值。
更新日期：2023-09-26
中文翻译：
灯盏乙素通过 Pdk-Pdc 轴改善线粒体葡萄糖氧化来挽救线粒体损伤
线粒体生物能缺陷及其导致的葡萄糖代谢低下是促进神经退行性变的关键病理生理调节因子。然而，目前还没有发现特定的潜在分子可以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。丙酮酸脱氢酶 (PDH) 复合物 (PDC) 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看门酶。本研究发现一种小分子灯盏花乙素（SG）能够显着缓解脑低灌注模型大鼠海马CA1区的神经病理改变，挽救异常线粒体的形态变化，恢复线粒体稳态。线粒体蛋白质组学、能量代谢监测和13 C 代谢流分析以 PDK2 上的 SG 活性为目标，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的敲低证实SG可以通过PDK-PDC轴挽救线粒体损伤，促进MMP水平并减少线粒体依赖性细胞凋亡。总的来说，本研究探索了新的治疗方法：PDK-PDC 轴治疗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治疗具有重要价值。
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