title: Mitochondrial aberrations in mucolipidosis Type IV.
abstract: Mucolipidosis type IV is a genetic lysosomal storage disease associated with degenerative processes in the brain, eye, and other tissues. Mucolipidosis type IV results from mutations in the gene MCOLN1, which codes for the TRP family ion channel, mucolipin 1. The connection between lysosomal dysfunction and degenerative processes in mucolipidosis type IV is unclear. Here we report that mucolipidosis type IV and several unrelated lysosomal storage diseases are associated with significant mitochondrial fragmentation and decreased mitochondrial Ca2+ buffering efficiency. The mitochondrial alterations observed in these lysosomal storage diseases are reproduced in control cells by treatment with lysosomal inhibitors and with the autophagy inhibitor 3-methyladenine. This suggests that inefficient autophagolysosomal recycling of mitochondria generates fragmented, effete mitochondria in mucolipidosis. Mitochondria accumulate that cannot properly buffer calcium fluxes in the cell. A decrease in mitochondrial Ca2+ buffering capacity in cells affected by these lysosomal storage diseases is associated with increased sensitivity to apoptosis induced by Ca2+-mobilizing agonists and executed via a caspase-8-dependent pathway. Deficient Ca2+ homeostasis may represent a common mechanism of degenerative cell death in several lysosomal storage diseases.
authors.affiliation: Department of Biological Science, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Jennings
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Zhu
authors.forename: Youssef
authors.initials: Y
authors.lastname: Rbaibi
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D001343:Autophagy; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053938:DNA Fragmentation; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007477:Ions; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009081:Mucolipidoses / Q000378:metabolism / Q000473:pathology*; D010587:Phagocytosis; D050053:TRPM Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels
chemical_list: D007477:Ions; C416674:MCOLN1 protein, human; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; C025946:3-methyladenine; D053181:Caspase 8; D000225:Adenine; D002118:Calcium