title: GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis.
abstract: Mitochondria-associated ER membranes, or MAMs, define the sites of endoplasmic reticulum/mitochondria juxtaposition that control Ca(2+) flux between these organelles. We found that in a mouse model of the human lysosomal storage disease GM1-gangliosidosis, GM1-ganglioside accumulates in the glycosphingolipid-enriched microdomain (GEM) fractions of MAMs, where it interacts with the phosphorylated form of IP3 receptor-1, influencing the activity of this channel. Ca(2+) depleted from the ER is then taken up by the mitochondria, leading to Ca(2+) overload in this organelle. The latter induces mitochondrial membrane permeabilization (MMP), opening of the permeability transition pore, and activation of the mitochondrial apoptotic pathway. This study identifies the GEMs as the sites of Ca(2+) diffusion between the ER and the mitochondria. We propose a new mechanism of Ca(2+)-mediated apoptotic signaling whereby GM1 accumulation at the GEMs alters Ca(2+) dynamics and acts as a molecular effector of both ER stress-induced and mitochondria-mediated apoptosis of neuronal cells.
authors.affiliation: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.forename: Ida
authors.initials: I
authors.lastname: Annunziata
authors.forename: Annette
authors.initials: A
authors.lastname: Patterson
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.forename: Elida
authors.initials: E
authors.lastname: Gomero
authors.forename: Joseph
authors.initials: J
authors.lastname: Opferman
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D016537:Gangliosidosis, GM1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; D005677:G(M1) Ganglioside; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D001616:beta-Galactosidase; D002118:Calcium