Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites
作者机构：Department of PharmacyCollege of PharmacySeoul National UniversitySeoulRepublic of Korea Research Institute of Pharmaceutical SciencesCollege of PharmacySeoul National UniversitySeoulRepublic of Korea BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education UnitCollege of Pharmacy and Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea Department of ChemistrySeoul National UniversitySeoulRepublic of Korea College of PharmacyChung-Ang UniversitySeoulRepublic of Korea Natural Product Informatics Research CenterKorea Institute of Science and Technology(KIST)Gangneung-siGangwon-doRepublic of Korea School of Life SciencesGwangju Institute of Science and Technology(GIST)GwangjuRepublic of Korea Department of BiochemistryCollege of MedicineDong-A UniversityBusanRepublic of Korea Global AI Drug Discovery CenterCollege of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea Interdisciplinary Program in Genetic EngineeringSeoul National UniversitySeoulRepublic of Korea
出 版 物：《Cancer Communications》 (癌症通讯（英文）)
年 卷 期：2024年第44卷第1期
页 面：47-75页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：This work was supported by Basic Science Research Pro-gram through the National Research Foundation of Korea(NRF)funded by the Ministry of Science ICT&Future Planning(NRF-2021R1A6A3A01087300 to JEK NRF-2021M3H9A2098553 to YL NRF-2022M3E5F3080873 to SC NRF-2022R1A4A1018900 to LKH NRF-2020R1A2C3008993 and NRF-2021M3A9D3024752 to JWL)
主 题：cholesterol fluorescent imaging glucose catabolism hepatocellular carcinogenesis mem-brane contact sites mitochondria function mitophagy oxidative phosphorylation protein-protein interaction tetraspanin
摘 要：Background:Transmembrane 4 L six family member 5(TM4SF5)translocates subcellularly and functions metabolically,although it is unclear how intracellu-lar TM4SF5 translocation is linked to metabolic *** is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of ***:Here,we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites(MLCSs),using in vitro cells and in vivo animal systems,via approaches by immunofluorescence,proximity labelling based proteomics analysis,organelle reconstitution ***:Upon extracellular glucose repletion following depletion,TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8(FKBP8)and lysosomal *** labeling showed molecular clustering of phospho-dynamic-related protein I(DRP1)and certain mitophagy receptors at TM4SF5-enriched MLCSs,leading to mitochondrial fis-sion and ***4SF5 bound NPC intracellular cholesterol transporter 1(NPC1)and free cholesterol,and mediated export of lysosomal cholesterol to mitochondria,leading to impaired oxidative phosphorylation but intact tri-carboxylic acid(TCA)cycle andβ-*** mouse models,hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria,both with positive relations to liver ***:Our findings suggested that TM4SF5-enriched MLCSs regu-late glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming,presumably while hepatocellular carcinogenesis,recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial repro-gramming to support biomolecule synthesis in addition to glycolytic energetics.
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