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

Summary

This mechanistic study identifies a lysosomal LRRC8 anion channel program that sets lysosomal pH and morphology, tunes PI3K–AKT–mTOR signaling, and governs systemic insulin sensitivity. Muscle-targeted LRRC8A motif mutation in knock-in mice led to adiposity, glucose intolerance, and insulin resistance with reduced muscle glucose uptake and glycogen incorporation.

Key Findings

• Endogenous LRRC8 subunits localize to a lysosomal subset in differentiated myotubes and regulate lysosomal pH, size, and number.
• LRRC8A controls leucine-stimulated mTOR signaling and lysosomal protein expression (LAMP2, P62, LC3B).
• LRRC8A L706A;L707A motif mutation recapitulates AKT signaling defects and altered lysosomal morphology/pH seen in LRRC8A knockout.
• Knock-in mice with LRRC8A motif mutation exhibit increased adiposity, impaired glucose tolerance, and insulin resistance with reduced skeletal muscle PI3K–AKT–mTOR signaling, glucose uptake, and glycogen incorporation.

Clinical Implications

Targeting LRRC8-dependent lysosomal function or its trafficking motif could modulate mTOR tone and insulin sensitivity, motivating drug discovery around lysosomal ion channels and biomarkers of lysosomal pH in metabolic disease.

Limitations

• Translational relevance to humans remains to be demonstrated; no pharmacologic LRRC8 modulation tested.
• Tissue-specific contributions beyond skeletal muscle were not fully dissected.

Future Directions

Develop selective LRRC8 modulators; define tissue-specific roles in liver/adipose; validate biomarkers of lysosomal pH and signaling in humans with insulin resistance.