PMID- 37935660 OWN - NLM STAT- MEDLINE DCOM- 20231109 LR - 20231110 IS - 2041-4889 (Electronic) VI - 14 IP - 11 DP - 2023 Nov 7 TI - Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes. PG - 722 LID - 10.1038/s41419-023-06249-2 [doi] LID - 722 AB - 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. CI - (c) 2023. The Author(s). FAU - Yao, Yuan AU - Yao Y AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. AD - Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. FAU - Shi, Jiaming AU - Shi J AD - Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. FAU - Zhang, Chunlai AU - Zhang C AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. FAU - Gao, Wei AU - Gao W AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. FAU - Huang, Ning AU - Huang N AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. FAU - Liu, Yaobei AU - Liu Y AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. FAU - Yan, Weiwen AU - Yan W AD - Department of Clinical Laboratory, Zibo Hospital of Traditional Chinese Medicine, Zibo, Shandong, China. FAU - Han, Yingguang AU - Han Y AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. FAU - Zhou, Wenjuan AU - Zhou W AUID- ORCID: 0000-0002-3042-2496 AD - Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. FAU - Kong, Liang AU - Kong L AUID- ORCID: 0000-0002-0495-9193 AD - Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. kongliang0115@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231107 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) RN - 0 (Histones) RN - 0 (Reactive Oxygen Species) RN - 72-89-9 (Acetyl Coenzyme A) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Humans MH - Mice MH - Animals MH - Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism MH - Histones/metabolism MH - *Diabetes Mellitus, Experimental/complications/genetics/metabolism MH - Reactive Oxygen Species/metabolism MH - Acetyl Coenzyme A/metabolism MH - Epigenesis, Genetic MH - Disease Models, Animal MH - Neurons/metabolism MH - *Hyperglycemia MH - Memory Disorders MH - Glucose/toxicity PMC - PMC10630521 COIS- The authors declare no competing interests. EDAT- 2023/11/08 00:41 MHDA- 2023/11/09 06:42 PMCR- 2023/11/07 CRDT- 2023/11/07 23:14 PHST- 2023/06/26 00:00 [received] PHST- 2023/10/25 00:00 [accepted] PHST- 2023/10/13 00:00 [revised] PHST- 2023/11/09 06:42 [medline] PHST- 2023/11/08 00:41 [pubmed] PHST- 2023/11/07 23:14 [entrez] PHST- 2023/11/07 00:00 [pmc-release] AID - 10.1038/s41419-023-06249-2 [pii] AID - 6249 [pii] AID - 10.1038/s41419-023-06249-2 [doi] PST - epublish SO - Cell Death Dis. 2023 Nov 7;14(11):722. doi: 10.1038/s41419-023-06249-2.