Determinants of lysosomal pH. Lysosomal acidification is dependent on V-ATPase, a large multimeric enzyme complex that transforms the energy of ATP hydrolysis into the movement of protons across the lysosome membrane. Electrogenic proton transport creates an electrical gradient that must be dissipated to establish the substantial chemical proton gradient. Electroneutrality can be maintained through the parallel influx of anions alongside protons. ClC-7, a chloride proton antiporter, and CFTR have been proposed to constitute the counter ion pathways in the lysosome membrane, as described in the text. The efflux of cations (C⁺) through distinct channels or transporters can also occur. Parallel proton leak pathways (dotted lines) are also known to exist and require continued V-ATPase activity to maintain a steady-state pH. Acidification kinetics are also contingent on the luminal buffering power (not depicted).