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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)47-75
Number of pages29
JournalCancer communications (London, England)
Issue number1
StatePublished - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of SUN YAT-SEN UNIVERSITY CANCER CENTER.


  • cholesterol
  • fluorescent imaging
  • glucose catabolism
  • hepatocellular carcinogenesis
  • membrane contact sites
  • mitochondria function
  • mitophagy
  • oxidative phosphorylation
  • protein-protein interaction
  • tetraspanin


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