{"doi":"10.1101/2024.09.22.614256","title":"Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism","abstract":"Abstract The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo , LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489042,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":585482,"name":"Yonghui Zhao","orcid":"0000-0002-0876-1002","position":1,"is_corresponding":false},{"id":303252,"name":"Litao Xie","orcid":null,"position":2,"is_corresponding":false},{"id":576227,"name":"Rahul Chadda","orcid":"0000-0001-6710-3985","position":3,"is_corresponding":false},{"id":1106186,"name":"Nihil Abraham","orcid":null,"position":4,"is_corresponding":false},{"id":1333944,"name":"Juan Hong","orcid":"0000-0003-1445-9130","position":5,"is_corresponding":false},{"id":1223452,"name":"Ethan Yang Feng","orcid":null,"position":6,"is_corresponding":false},{"id":1333945,"name":"John D. Tranter","orcid":"0009-0006-6884-7154","position":7,"is_corresponding":false},{"id":413233,"name":"David R. Rawnsley","orcid":"0000-0002-1620-8637","position":8,"is_corresponding":false},{"id":413670,"name":"Haiyan Liu","orcid":"0000-0002-2500-4601","position":9,"is_corresponding":false},{"id":1334447,"name":"Kyla M Henry","orcid":null,"position":10,"is_corresponding":false},{"id":245889,"name":"Gretchen A. Meyer","orcid":"0000-0001-9268-3993","position":11,"is_corresponding":false},{"id":273657,"name":"Meiqin Hu","orcid":"0000-0002-3953-5868","position":12,"is_corresponding":false},{"id":254906,"name":"Haoxing Xu","orcid":"0000-0003-3561-4654","position":13,"is_corresponding":false},{"id":297596,"name":"Antentor Hinton","orcid":"0000-0002-7730-952X","position":14,"is_corresponding":false},{"id":301601,"name":"Chad E. Grueter","orcid":"0000-0001-8950-742X","position":15,"is_corresponding":false},{"id":153753,"name":"E. Dale Abel","orcid":"0000-0001-5290-0738","position":16,"is_corresponding":false},{"id":297601,"name":"Andrew W. Norris","orcid":"0000-0001-8396-9543","position":17,"is_corresponding":false},{"id":238348,"name":"Abhinav Diwan","orcid":"0000-0001-7554-4772","position":18,"is_corresponding":false},{"id":301602,"name":"Rajan Sah","orcid":"0000-0003-1092-1244","position":19,"is_corresponding":false},{"id":301598,"name":"Ashutosh Kumar","orcid":"0000-0002-2623-0416","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:23.929823Z","pmid":"39386592","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}