한빛사논문
Ji Eon Kim 1 2, So-Young Park 3, Chulhwan Kwak 4, Yoonji Lee 5, Dae-Geun Song 6, Jae Woo Jung 1, Haesong Lee 1, Eun-Ae Shin 1, Yangie Pinanga 1, Kyung-Hee Pyo 1, Eun Hae Lee 1, Wonsik Kim 1, Soyeon Kim 1, Chang-Duck Jun 7, Jeanho Yun 8, Sun Choi 9, Hyun-Woo Rhee 4, Kwang-Hyeon Liu 3 *, Jung Weon Lee 1 2 10 *
1Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
3BK21 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.
4Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
5College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
6Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, Republic of Korea.
7School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
8Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea.
9Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
10Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
*Corresponding authors: correspondence to Kwang-Hyeon Liu or Jung Weon Lee
Abstract
Background
Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular 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 fission 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 tricarboxylic acid (TCA) cycle and β-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 regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.
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