Regulation of organelle acidity

Intracellular organelles have characteristic pH ranges that are set and mai ntained by a balance between ion pumps, leaks. and internal ionic equilibri a. Previously a thermodynamic study by Rybak et al. (Rybak, S.. F. Lanni, a nd R. Murphy, 1997. Biophys. J. 73:674-687) identified the key elements inv olved in pH regulation: however; recent experiments show that cellular comp artments are not in thermodynamic equilibrium. We present here a nonequilib rium model of lumenal acidification based on the interplay of ion pumps and channels, the physical properties of the lumenal matrix, and the organelle geometry. The model successfully predicts experimentally measured steady-s tate and transient pH values and membrane potentials. We conclude that morp hological differences among organelles are insufficient to explain the wide range of pHs present in the cell. Using sensitivity analysis, we quantifie d the influence of pH regulatory elements on the dynamics of acidification. We found that V-ATPase proton pump and proton leak densities are the two p arameters that most strongly influence resting pH. Additionally we modeled the pH response or the Golgi complex to varying external solutions, and our findings suggest that the membrane is permeable to more than one dominant counter ion. From this data, we determined a Golgi complex proton permeabil ity of 8.1 x 10(-6) cm/s. Furthermore. we analyzed the early-to-late transi tion in the endosomal pathway where Na,K-ATPases have been shown to limit a cidification by an entire pH unit. Our model supports the role of the Na.K- ATPase in regulating endosomal pH by affecting the membrane potential, Howe ver experimental data ran only be reproduced by (1) positing the existence of a hypothetical voltage-gated chloride channel or (2) that newly formed v esicles have especially high potassium concentrations and small chloride co nductance.