Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism

Area of Science:

• Cell Biology
• Metabolic Signaling
• Molecular Mechanisms

Background:

• Lysosomes integrate nutrient sensing with anabolic signaling pathways like PI3K-AKT-mTOR.
• The leucine-rich repeat-containing 8 (LRRC8) channel complex is a lysosomal anion channel implicated in cellular growth and metabolism.

Purpose of the Study:

• To define the role of endogenous LRRC8 subunits in lysosomal function and metabolic regulation.
• To investigate the impact of LRRC8A dysfunction on skeletal muscle and systemic glucose homeostasis.

Main Methods:

• Localization of endogenous LRRC8 subunits in differentiated myotubes.
• Functional analysis of LRRC8A mutations (LRRC8A-L706A;L707A) in myotubes and knock-in mice.
• Assessment of lysosomal parameters (size, number, pH, protein expression) and PI3K-AKT-mTOR signaling pathways.

Main Results:

• LRRC8A regulates leucine-stimulated mTOR signaling, lysosomal morphology, pH, and protein expression (LAMP2, P62, LC3B).
• Mutating a key LRRC8A motif recapitulates lysosomal and signaling defects observed in LRRC8A knockout cells.
• LRRC8A-L706A;L707A knock-in mice display increased adiposity, impaired glucose tolerance, and insulin resistance.

Conclusions:

• Lysosomal LRRC8A plays a critical role in regulating lysosomal function and metabolic signaling.
• LRRC8A is essential for maintaining systemic glucose homeostasis and insulin sensitivity.
• Targeting lysosomal LRRC8 channels may offer therapeutic strategies for metabolic disorders.