title: Evidence of lysosomal membrane permeabilization in mucopolysaccharidosis type I: rupture of calcium and proton homeostasis.
abstract: Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of alpha-iduronidase (IDUA), which leads to intralysosomal accumulation of glysosaminoglycans. Patients with MPS I present a wide range of clinical manifestations, but the mechanisms by which these alterations occur are still not fully understood. Genotype-phenotype correlations have not been well established for MPS I; hence, it is likely that secondary and tertiary alterations in cellular metabolism and signaling may contribute to the physiopathology of the disease. The aim of this study was to analyze Ca(2+) and H(+) homeostasis, lysosomal leakage of cysteine proteases, and apoptosis in a murine model of MPS I. After exposition to specific drugs, cells from Idua-/- mice were shown to release more Ca(2+) from the lysosomes and endoplasmic reticulum than Idua+/+ control mice, suggesting a higher intraorganelle store of this ion. A lower content of H(+) in the lysosomes and in the cytosol was found in cells from Idua-/- mice, suggesting an alteration of pH homeostasis. In addition, Idua-/- cells presented a higher activity of cysteine proteases in the cytosol and an increased rate of apoptotic cells when compared to the control group, indicating that lysosomal membrane permeabilization might occur in this model. Altogether, our results suggest that secondary alterations-as changes in Ca(2+) and H(+) homeostasis and lysosomal membrane permeabilization-may contribute for cellular damage and death in the physiopathology of MPS I.
authors.affiliation: CREIM, Department of Pediatrics, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Vanessa Gonçalves
authors.initials: VG
authors.lastname: Pereira
authors.forename: Marcos L
authors.initials: ML
authors.lastname: Gazarini
authors.forename: Lara Cheliz
authors.initials: LC
authors.lastname: Rodrigues
authors.forename: Flávia Helena
authors.initials: FH
authors.lastname: da Silva
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Han
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Martins
authors.forename: Ivarne L S
authors.initials: IL
authors.lastname: Tersariol
authors.forename: Vânia
authors.initials: V
authors.lastname: D'Almeida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D057056:Cysteine Proteases / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000503:physiopathology; D011522:Protons
chemical_list: D011522:Protons; D057056:Cysteine Proteases; D002118:Calcium