Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites  

作　　者：Ji Eon Kim So-Young Park Chulhwan Kwak Yoonji Lee Dae-Geun Song Jae Woo Jung Haesong Lee Eun-Ae Shin Yangie Pinanga Kyung-hee Pyo Eun Hae Lee Wonsik Kim Soyeon Kim Chang-Duck Jun Jeanho Yun Sun Choi Hyun-Woo Rhee Kwang-Hyeon Liu Jung Weon Lee 

机构地区：[1]Department of Pharmacy,College of Pharmacy,Seoul National University,Seoul,Republic of Korea [2]Research Institute of Pharmaceutical Sciences,College of Pharmacy,Seoul National University,Seoul,Republic of Korea [3]BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit,College of Pharmacy and Research Institute of Pharmaceutical Sciences,Kyungpook National University,Daegu,Republic of Korea [4]Department of Chemistry,Seoul National University,Seoul,Republic of Korea [5]College of Pharmacy,Chung-Ang University,Seoul,Republic of Korea [6]Natural Product Informatics Research Center,Korea Institute of Science and Technology(KIST),Gangneung-si,Gangwon-do,Republic of Korea [7]School of Life Sciences,Gwangju Institute of Science and Technology(GIST),Gwangju,Republic of Korea [8]Department of Biochemistry,College of Medicine,Dong-A University,Busan,Republic of Korea [9]Global AI Drug Discovery Center,College of Pharmacy and Graduate School of Pharmaceutical Sciences,Ewha Womans University,Seoul,Republic of Korea [10]Interdisciplinary Program in Genetic Engineering,Seoul National University,Seoul,Republic of Korea

出　　处：《Cancer Communications》2024年第1期47-75,共29页癌症通讯（英文）

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).

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 contexts.It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.Methods: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 etc.Results:Upon extracellular glucose repletion following depletion,TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8(FKBP8)and lysosomal TM4SF5.Proximity 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 autophagy.TM4SF5 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-oxidation.In mouse models,hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria,both with positive relations to liver malignancy.Conclusions: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.

关 键 词：CHOLESTEROL fluorescent imaging glucose catabolism hepatocellular carcinogenesis mem-brane contact sites mitochondria function mitophagy oxidative phosphorylation protein-protein interaction TETRASPANIN 

分 类 号：R73[医药卫生—肿瘤]