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

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.

Differential ligand binding/trafficking for distinct CTLA-4 fates: is it an expandable mechanism?

In a recent issue of Nature Immunology,Kennedy et al.reported that CTLA-4(CD152)differentially targets two distinct ligands,CD80 and CD86,on antigen-presenting cells(APCs)for destruction or recycling following transendocytosis(TE),resulting in separate fates for CTLA-4 on T_(reg) cells and thereby regulating autoimmunity.Mechanistically,whereas CTLA-4 tightly binds CD80 for TE and causes ubiquitination and trafficking to late endosomes and lysosomes for degradation,CTLA-4 weakly binds CD86 for TE,resulting in dissociation under acidic conditions(pH<6)and recycling of CTLA-4 to the plasma membrane for further CD86 removal.Therefore,CD86 targeting by CTLA-4 regulates T-cell function in autoimmunity[1]and presumably immune surveillance of cancer cells(Fig.1).