PMID- 37726499 OWN - NLM STAT- Publisher LR - 20230919 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) DP - 2023 Sep 20 TI - Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models. LID - 10.1007/s12035-023-03621-3 [doi] AB - Mitochondrial dysfunction is one of the hallmarks in the pathophysiology of prion disease and other neurodegenerative diseases. Various metabolic dysfunctions are identified and considered to contribute to the progression of some types of neurodegenerative diseases. In this study, we evaluated the status of glycolysis pathway in prion-infected rodent and cell models. The levels of the key enzymes, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) were significantly increased, accompanying with markedly downregulated mitochondrial complexes. Double-stained IFAs revealed that the increased HK2 and PFK distributed widely in GFAP-, Iba1-, and NeuN-positive cells. We also identified increased levels of AMP-activated protein kinase (AMPK) and the downstream signaling. Changes of AMPK activity in prion-infected cells by the AMPK-specific inhibitor or activator induced the corresponding alterations not only in the downstream signaling, but also the expressions of three key kinases in glycolysis pathway and the mitochondrial complexes. Transient removal or complete clearance of prion propagation in the prion-infected cells partially but significantly reversed the increases of the key enzymes in glycolysis, the upregulation of AMPK signaling pathway, and the decreases of the mitochondrial complexes. Measurements of the cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) showed lower OCR and higher ECAR in prion-infected cell line, which were sufficiently reversed by clearance of prion propagation. Those data indicate a metabolic reprogramming from oxidative phosphorylation to glycolysis in the brains during the progression of prion disease. Accumulation of PrP(Sc) is critical for the switch to glycolysis, largely via activating AMPK pathway. CI - (c) 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Fan, Qin AU - Fan Q AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Xiao, Kang AU - Xiao K AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - A, Ruhan AU - A R AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Gao, Li-Ping AU - Gao LP AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Wu, Yue-Zhang AU - Wu YZ AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Chen, Dong-Dong AU - Chen DD AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Hu, Chao AU - Hu C AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Jia, Xiao-Xi AU - Jia XX AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Liu, Chu-Mou AU - Liu CM AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Liu, Xin AU - Liu X AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. FAU - Chen, Cao AU - Chen C AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. AD - Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China. FAU - Shi, Qi AU - Shi Q AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. shiqi76@126.com. AD - China Academy of Chinese Medical Sciences, Beijing, China. shiqi76@126.com. FAU - Dong, Xiao-Ping AU - Dong XP AUID- ORCID: 0000-0002-6282-9864 AD - National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Disease, NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. dongxp238@sina.com. AD - Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China. dongxp238@sina.com. AD - China Academy of Chinese Medical Sciences, Beijing, China. dongxp238@sina.com. AD - Shanghai Institute of Infectious Disease and Biosafety, Shanghai, China. dongxp238@sina.com. LA - eng GR - 81630062/Chinese National Natural Science Foundation Grants/ GR - 2019SKLID501/the State Key Laboratory for Infectious Disease Prevention and Control, China CDC/ GR - 2019SKLID603/the State Key Laboratory for Infectious Disease Prevention and Control, China CDC/ GR - 2019SKLID307/the State Key Laboratory for Infectious Disease Prevention and Control, China CDC/ PT - Journal Article DEP - 20230920 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 SB - IM OTO - NOTNLM OT - AMPK signaling OT - Glycolysis OT - Mitochondrial complex OT - Prion EDAT- 2023/09/20 00:43 MHDA- 2023/09/20 00:43 CRDT- 2023/09/19 23:33 PHST- 2023/02/19 00:00 [received] PHST- 2023/08/28 00:00 [accepted] PHST- 2023/09/20 00:43 [medline] PHST- 2023/09/20 00:43 [pubmed] PHST- 2023/09/19 23:33 [entrez] AID - 10.1007/s12035-023-03621-3 [pii] AID - 10.1007/s12035-023-03621-3 [doi] PST - aheadofprint SO - Mol Neurobiol. 2023 Sep 20. doi: 10.1007/s12035-023-03621-3.