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TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Mar 17; Vol. 281 (11), pp. 7294-301. Date of Electronic Publication: 2005 Dec 16. - Publication Year :
- 2006
-
Abstract
- Mucolipidosis type IV (MLIV) is caused by mutations in the ion channel mucolipin 1 (TRP-ML1). MLIV is typified by accumulation of lipids and membranous materials in intracellular organelles, which was hypothesized to be caused by the altered membrane fusion and fission events. How mutations in TRP-ML1 lead to aberrant lipolysis is not known. Here we present evidence that MLIV is a metabolic disorder that is not associated with aberrant membrane fusion/fission events. Thus, measurement of lysosomal pH revealed that the lysosomes in TRP-ML1(-/-) cells obtained from the patients with MLIV are over-acidified. TRP-ML1 can function as a H(+) channel, and the increased lysosomal acidification in TRP-ML1(-/-) cells is likely caused by the loss of TRP-ML1-mediated H(+) leak. Measurement of lipase activity using several substrates revealed a marked reduction in lipid hydrolysis in TRP-ML1(-/-) cells, which was rescued by the expression of TRP-ML1. Cell fractionation indicated specific loss of acidic lipase activity in TRP-ML1(-/-) cells. Furthermore, dissipation of the acidic lysosomal pH of TRP-ML1(-/-) cells by nigericin or chloroquine reversed the lysosomal storage disease phenotype. These findings provide a new mechanism to account for the pathogenesis of MLIV.
- Subjects :
- Acridine Orange pharmacology
Calcium chemistry
Calcium metabolism
Calcium Signaling
Carboxylic Acids pharmacology
Cell Line
Cell Membrane metabolism
Chloroquine chemistry
Chromatography, Thin Layer
Humans
Hydrogen-Ion Concentration
Hydrolases chemistry
Hydrolysis
Ionophores chemistry
Lipase chemistry
Lipids chemistry
Lysosomal Storage Diseases metabolism
Lysosomes chemistry
Magnesium chemistry
Membrane Fusion
Microscopy, Electron
Microscopy, Fluorescence
Models, Biological
Mutation
Phenotype
Protons
Subcellular Fractions metabolism
TRPM Cation Channels metabolism
Transient Receptor Potential Channels
Lysosomes metabolism
Sterol Esterase chemistry
TRPM Cation Channels chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16361256
- Full Text :
- https://doi.org/10.1074/jbc.M508211200