GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis.
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.
Sano
Renata
R
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Annunziata
Ida
I
Patterson
Annette
A
Moshiach
Simon
S
Gomero
Elida
E
Opferman
Joseph
J
Forte
Michael
M
d'Azzo
Alessandra
A
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
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