Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism
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.
Authors
- David R. Rawnsley (ORCID: https://orcid.org/0000-0002-1620-8637)
- Antentor Hinton (ORCID: https://orcid.org/0000-0002-7730-952X)
- John D. Tranter (ORCID: https://orcid.org/0009-0006-6884-7154)
- E. Dale Abel (ORCID: https://orcid.org/0000-0001-5290-0738)
- Chad E. Grueter (ORCID: https://orcid.org/0000-0001-8950-742X)
- Rahul Chadda (ORCID: https://orcid.org/0000-0001-6710-3985)
- Andrew W. Norris (ORCID: https://orcid.org/0000-0001-8396-9543)
- Abhinav Diwan (ORCID: https://orcid.org/0000-0001-7554-4772)
- Meiqin Hu (ORCID: https://orcid.org/0000-0002-3953-5868)
- Ashutosh Kumar (ORCID: https://orcid.org/0000-0002-2623-0416)
- Gretchen A. Meyer (ORCID: https://orcid.org/0000-0001-9268-3993)
- Rajan Sah (ORCID: https://orcid.org/0000-0003-1092-1244)
- Haoxing Xu (ORCID: https://orcid.org/0000-0003-3561-4654)
- Haiyan Liu (ORCID: https://orcid.org/0000-0002-3154-8285)
- Yonghui Zhao (ORCID: https://orcid.org/0000-0002-6192-4130)
- Nihil Abraham
- Juan Hong (ORCID: https://orcid.org/0000-0002-7894-8403)
- Litao Xie
- Ethan Yang Feng
- Ryan Mikami
- K. Henry (ORCID: https://orcid.org/0009-0007-1846-0725)
Institutions
- University of Iowa (US)
- University of California, Los Angeles (US)
- Vanderbilt University (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- Fraternal Order of Eagles (US)
- St. Louis VA Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1126/sciadv.adt6366
- Citations
- 4
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 4.47