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

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Cancer Communications 2024年第1期44卷 47-75页

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 Department of Pharmacy College of PharmacySeoul National UniversitySeoulRepublic of Korea Research Institute of Pharmaceutical Sciences College of PharmacySeoul National UniversitySeoulRepublic of Korea bk21 four community-based intelligent novel drug discovery education unit College of Pharmacy and Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea Department of Chemistry Seoul National UniversitySeoulRepublic of Korea College of Pharmacy Chung-Ang UniversitySeoulRepublic of Korea Natural Product Informatics Research Center Korea Institute of Science and Technology(KIST)Gangneung-siGangwon-doRepublic of Korea School of Life Sciences Gwangju Institute of Science and Technology(GIST)GwangjuRepublic of Korea Department of Biochemistry College of MedicineDong-A UniversityBusanRepublic of Korea Global AI drug discovery Center College of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea Interdisciplinary Program in Genetic Engineering Seoul National UniversitySeoulRepublic of Korea

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.

关键词： cholesterol fluorescent imaging glucose catabolism hepatocellular carcinogenesis mem-brane contact sites mitochondria function mitophagy oxidative phosphorylation protein-protein interaction tetraspanin

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novel Time-dependent Multi-omics Integration in Sepsis-associated Liver Dysfunction

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Genomics, Proteomics & Bioinformatics 2023年第6期21卷 1101-1116页

作者： Ann-Yae Na Hyojin Lee Eun Ki Min Sanjita Paudel So Young Choi HyunChae Sim Kwang-Hyeon Liu Ki-Tae Kim Jong-Sup Bae Sangkyu Lee Research Institute of Pharmaceutical Sciences Kyungpook National UniversityDaegu 41566Republic of Korea Department of Environmental Engineering Seoul National University of Science and TechnologySeoul 01811Republic of Korea bk21 four community-based intelligent novel drug discovery education unit College of PharmacyKyungpook National UniversityDaegu 41566Republic of Korea School of Pharmacy Sungkyunkwan UniversitySuwon 16419Republic of Korea

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease ***,it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical ***,we conducted a time-dependent multi-omics integration(TDMI)in a sepsis-associated liver dysfunction(SALD)*** successfully deduced the relation of the Toll-like receptor 4(TLR4)pathway with *** TLR4 is a critical factor in sepsis progression,it is not specified in single-omics analyses but only in the TDMI *** finding indicates that the TDMI-based approach is more advantageous than single-omics analyses in terms of exploring the underlying pathophysiological mechanism of ***,TDMI-based approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology,health,and diseases,thus allowing the identification of promising candidates for therapeutic strategies.

关键词： Multi-omics Omics technology Sepsis-associated liver dysfunction Single omics Time-dependent integration

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