1. Lysosomal pathology and osteopetrosis upon loss of [H.sup.+]-driven lysosomal [Cl.sup.-] accumulation
- Author
-
Weinert, Stefanie, Jabs, Sabrina, Supanchart, Chayarop, Schweizer, Michaela, Gimber, Niclas, Richter, Martin, Rademann, Jorg, Stauber, Tobias, Kornak, Uwe, and Jentsch, Thomas J.
- Subjects
Osteopetrosis -- Development and progression ,Lysosomes -- Physiological aspects ,Lysosomes -- Health aspects ,Chloride channels -- Health aspects ,Ion exchange -- Health aspects ,Science and technology - Abstract
During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion ([Cl.sup.-]) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates [Cl.sup.-]/proton ([H.sup.+]) exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoup|ed (unc) [Cl.sup.-] conductor. Despite maintaining lysosomal conductance and normal lysosomal pH, these [Clcn7.sup.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.sup.-]/[H.sup.+] exchange can be taken over by a [Cl.sup.-] conductance. This conductance was even deleterious in [Clcn7.sup.+/unc] mice. [Clcn7.sup.-/-] and [Clcn7.sup.unc/unc] mice accumulated less [Cl.sup.-] in lysosomes than did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes. 10.1126/science.1188072
- Published
- 2010
- Full Text
- View/download PDF