A model of lysosomal pH regulation

• DOI: 10.1085/jgp.201210930
• Publication Date: 2013-05-27T15:17:47Z
• Authors: Yoichi Ishida; Smita Nayak; Joseph A. Mindell; Michael Grabe
• Keywords: 0303 health sciences; Action Potentials; Hydrogen-Ion Concentration; Models, Biological; 03 medical and health sciences; Chloride Channels; Mutation; Potassium; Humans; Protons; Lysosomes; Research Articles; HeLa Cells

Lysosomes must maintain an acidic luminal pH to activate hydrolytic enzymes and degrade internalized macromolecules. Acidification requires the vacuolar-type H+-ATPase pump protons into lumen a counterion flux neutralize membrane potential created by proton accumulation. Early experiments suggested that was chloride, more recently pathway consistent with ClC-7 Cl–/H+ antiporter identified. However, reports steady-state is unaffected in knockout mice raise questions regarding identity of carrier counterion. Here, we measure current–voltage characteristics mammalian antiporter, use its transport properties, together other key ion regulating elements, construct mathematical model lysosomal regulation. We show results vitro lysosome can only be explained presence ClC-7, promotes greater acidification than Cl–, K+, or Na+ channels. Our models predict strikingly different K+ dynamics depending on major pathways. given lack experimental data concerning vivo, cannot definitively rule out any mechanism, but does provide concrete predictions for additional would clarify carrier.