1. Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation.
- Author
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Weinert S, Jabs S, Supanchart C, Schweizer M, Gimber N, Richter M, Rademann J, Stauber T, Kornak U, and Jentsch TJ
- Subjects
- Animals, Bone and Bones pathology, Cells, Cultured, Chloride Channels genetics, Gene Knock-In Techniques, Hair Color, Hippocampus pathology, Hydrogen-Ion Concentration, Lysosomal Storage Diseases metabolism, Lysosomal Storage Diseases pathology, Membrane Potentials, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mutant Proteins metabolism, Osteoclasts metabolism, Osteoclasts pathology, Osteopetrosis pathology, Phenotype, Point Mutation, Chloride Channels metabolism, Chlorides metabolism, Lysosomes metabolism, Osteopetrosis metabolism, Protons
- Abstract
During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion (Cl-) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates Cl-/proton (H+) exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled (unc) Cl- conductor. Despite maintaining lysosomal conductance and normal lysosomal pH, these Clcn7(unc/unc) mice showed lysosomal storage disease like mice lacking ClC-7. However, their osteopetrosis was milder, and they lacked a coat color phenotype. Thus, only some roles of ClC-7 Cl-/H+ exchange can be taken over by a Cl- conductance. This conductance was even deleterious in Clcn7(+/unc) mice. Clcn7(-/-) and Clcn7(unc/unc) mice accumulated less Cl- in lysosomes than did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.
- Published
- 2010
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