Cell reportsJul 18, 2026

TTYH3 controls chloride flow in lysosomes and affects their fusion, cell recycling, and aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 19, 2026

Abstract

TTYH3 regulates lysosomal chloride permeability and is associated with significantly enlarged lysosomes.

TTYH3 mediates the movement of chloride out of lysosomes, affecting their function.
Overexpression of TTYH3 promotes lysosomal fusion through specific cellular pathways.
Inhibition of the AKT/mTOR signaling pathway by TTYH3 enhances autophagy.
Activation of the ERK pathway by TTYH3 reduces cellular senescence.
TTYH3 expression may alleviate symptoms linked to lysosomal storage diseases caused by CLN7 deficiencies.

Simplified

Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca²⁺/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

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PubMed

TTYH3 controls chloride flow in lysosomes and affects their fusion, cell recycling, and aging

Abstract

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