Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes.
Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes.
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DOI：
10.1038/s41419-023-06249-2
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发表时间：
2023-11-07
影响因子：
9
通讯作者：
Kong, Liang
中科院分区：
文献类型：
--
作者：
Yao, Yuan;Shi, Jiaming;Zhang, Chunlai;Gao, Wei;Huang, Ning;Liu, Yaobei;Yan, Weiwen;Han, Yingguang;Zhou, Wenjuan;Kong, Liang
高血糖引起的糖代谢异常是糖尿病(DM)患者神经退行性变和认知功能障碍的原因之一。丙酮酸脱氢酶激酶(PDK)-乳酸轴被认为是代谢重编程与神经系统疾病发病过程之间的关键环节。然而，它在糖尿病神经病变中的作用尚不清楚。在此，我们发现在高糖(HG)刺激的原代神经元和Neuro-2a细胞系中，PDK1和丙酮酸脱氢酶(PDH)的磷酸化明显增加。乙酰辅酶A作为中枢代谢中间体，在HG状态下可能通过组蛋白H3K9乙酰化修饰促进PDK1的表达。对PDK1表达的表观遗传调控提供了一种有效的负反馈模式，以应对HG环境引发的线粒体代谢超载。而链脲佐菌素(STZ)诱导的糖尿病小鼠海马神经元PDK1表达减少。我们的数据表明，PDK1的表达还依赖于HG条件下低氧诱导因子-1(HIF-1)的转录激活。然而，HIF-1在糖尿病小鼠的海马区显著减少，这可能解释了PDK1在体内的相反表达。重要的是，PDK1的过表达减少了HG诱导的活性氧(ROS)的产生和神经元的凋亡。增强海马区PDK1的表达可改善STZ诱导的小鼠认知障碍和神经元变性。总之，我们的研究表明，乙酰辅酶A诱导的组蛋白乙酰化和HIF-1都是直接表达PDK1所必需的，增强PDK1可能对糖尿病小鼠的认知恢复具有保护作用。PDK1对高血糖诱导的神经元损伤和记忆丧失的保护作用示意图。在依赖乙酰辅酶A的组蛋白乙酰化修饰中，高糖增强了PDK1的表达，以避免线粒体代谢超载和ROS释放。然而，在高血糖条件下，HIF-1的减少可能会损害PDK1的上调。过表达PDK1可预防糖尿病小鼠高血糖诱导的海马神经元损伤和记忆丧失。
Hyperglycemia-induced aberrant glucose metabolism is a causative factor of neurodegeneration and cognitive impairment in diabetes mellitus (DM) patients. The pyruvate dehydrogenase kinase (PDK)–lactic acid axis is regarded as a critical link between metabolic reprogramming and the pathogenic process of neurological disorders. However, its role in diabetic neuropathy remains unclear. Here, we found that PDK1 and phosphorylation of pyruvate dehydrogenase (PDH) were obviously increased in high glucose (HG)-stimulated primary neurons and Neuro-2a cell line. Acetyl-coA, a central metabolic intermediate, might enhance PDK1 expression via histone H3K9 acetylation modification in HG condition. The epigenetic regulation of PDK1 expression provided an available negative feedback pattern in response to HG environment-triggered mitochondrial metabolic overload. However, neuronal PDK1 was decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Our data showed that the expression of PDK1 also depended on the hypoxia-inducible factor-1 (HIF-1) transcriptional activation under the HG condition. However, HIF-1 was significantly reduced in the hippocampus of diabetic mice, which might explain the opposite expression of PDK1 in vivo. Importantly, overexpression of PDK1 reduced HG-induced reactive oxygen species (ROS) generation and neuronal apoptosis. Enhancing PDK1 expression in the hippocampus ameliorated STZ-induced cognitive impairment and neuronal degeneration in mice. Together, our study demonstrated that both acetyl-coA-induced histone acetylation and HIF-1 are necessary to direct PDK1 expression, and enhancing PDK1 may have a protective effect on cognitive recovery in diabetic mice. Schematic representation of the protective effect of PDK1 on hyperglycemia-induced neuronal injury and memory loss. High glucose enhanced the expression of PDK1 in an acetyl-coA-dependent histone acetylation modification to avoid mitochondrial metabolic overload and ROS release. However, the decrease of HIF-1 may impair the upregulation of PDK1 under hyperglycemia condition. Overexpression of PDK1 prevented hyperglycemia-induced hippocampal neuronal injury and memory loss in diabetic mice.
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DOI：
10.1152/ajprenal.00029.2017
发表时间：
2017-08-01
影响因子：
4.2
作者：
Deb, Dilip K.;Chen, Yinyin;Li, Yan Chun
通讯作者：
Li, Yan Chun
影响因子：
7.2
作者：
Ni, Hongzao;Li, Jinxiao;Zhou, Botao
通讯作者：
Zhou, Botao
ATG4B S-亚硝化介导的自噬损伤会导致高血糖反应的神经毒性。
影响因子：
13.3
作者：
Li, Yazi;Zhang, Yuying;Chen, Chang
通讯作者：
Chen, Chang
影响因子：
21.3
作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
通讯作者：
Bolanos, Juan P.
影响因子：
4.8
作者：
Newington, Jordan T.;Rappon, Tim;Cumming, Robert C.
通讯作者：
Cumming, Robert C.