Journal article
Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism
Science advances, Vol.11(39), eadt6366
09/26/2025
DOI: 10.1126/sciadv.adt6366
PMCID: PMC12466849
PMID: 41004571
Abstract
The lysosome integrates anabolic signaling 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 signaling, 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 that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.
Details
- Title: Subtitle
- Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism
- Creators
- Ashutosh Kumar - Washington University in St. LouisYonghui Zhao - Washington University in St. LouisLitao Xie - Washington University in St. LouisRahul Chadda - Washington University in St. LouisJohn D Tranter - Washington University in St. LouisRyan T Mikami - Washington University in St. LouisNihil Abraham - Washington University in St. LouisJuan Hong - Washington University in St. LouisEthan Feng - Washington University in St. LouisDavid R Rawnsley - Washington University in St. LouisHaiyan Liu - Washington University in St. LouisKayla M Henry - University of IowaGretchen Meyer - Washington University in St. LouisMeiqin Hu - University of MichiganHaoxing Xu - University of MichiganAntentor Hinton Jr - Vanderbilt UniversityChad E Grueter - University of IowaE Dale Abel - University of IowaAndrew W Norris - Fraternal Order of EaglesAbhinav Diwan - Washington University in St. LouisRajan Sah - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.11(39), eadt6366
- DOI
- 10.1126/sciadv.adt6366
- PMID
- 41004571
- PMCID
- PMC12466849
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE; WASHINGTON
- Grant note
- NIH NIDDK: R01DK106009, R01DK126068, R01DK127080, R01-DK115791 NIH NHLBI: R01HL168600, R01HL107594, R01HL108379, K08HL163469 Department of Veteran Affairs: I01 BX005072, I01BX004235, I01BX005065, I01BX005981 CZI Science Diversity Leadership grant: 2022-253529
This work was supported by NIH NIDDK R01DK106009 (R.S.), R01DK126068 (R.S.), R01DK127080 (R.S.), and R01-DK115791 (A.W.N.); NIH NHLBI R01HL168600 (R.S.), R01HL107594 (A.D.), R01HL168600 (A.D.), R01HL108379 (E.D.A.), and K08HL163469 (D.R.R.); Department of Veteran Affairs I01 BX005072 (R.S.), I01BX004235 (A.D.), I01BX005065 (A.D.), and I01BX005981 (A.D.); and CZI Science Diversity Leadership grant (2022-253529, A.H.J.).
- Language
- English
- Date published
- 09/26/2025
- Academic Unit
- Endocrinology and Diabetes; Stead Family Department of Pediatrics; Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984966331802771
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