The lysosome is a membrane-bound compartment that digests macromolecules and cellular debris. To function properly, lysosomes must maintain an acidic environment (pH 4.5-5.0), generated by the proton-pumping action of a v-type H+ ATPase. However, since the ATPase is highly electrogenic, the voltage generated by its action must be dissipated by another ion movement, known as the ‘counterion pathway.’ It has been recently revealed that acidification in mouse liver lysosomes is dependent on the presence of Cl-, and is minimally affected by K+, indicating that Cl- serves as a counterion. Liver specific knockout of ClC-7, a gene for the lysosomal Cl-/H+ antiporter, abolishes H+-coupled Cl- transport in isolated liver lysosomes, implying ClC-7 acting as the primary counterion pathway in this system, also abolishing ATP-driven acidification in these organelles. However, when measuring lysosomal pH in primary hepatocytes, the knockout mice show no substantial lysosomal pH change compared wild type, revealing important differences between these experimental systems. It has been suggested that mammalian target of rapamycin (mTOR) complex dictates amino acid homeostasis for cell growth and regulates the lysosome's membrane potential and pH stability. Loss of mTOR regulation by knocking out of Tuberous sclerosis complex (TSC) leads to an increase in mouse liver size. Interestingly, liver specific ClC-7 KO mouse shows ∼30% increases of liver and body weight comparing to WT, a striking correlation. Indeed, we find that mTOR in liver-specific KO ClC-7 mouse becomes fasting-resistant and expresses at higher levels compared to that of WT. These observations are similar with the phenotype of TSC KO mouse. Given the suggested effects of the mTOR pathway on lysosomal ion channels, it is possible that mTOR changes account for the compensatory changes observed in living hepatocytes.