GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis.

[gm1 gangliosidosis]

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 GM 1 -gangliosidosis , GM 1 -ganglioside accumulates in the glycosphingolipid-enriched microdomain (GEM ) fractions of MAMs , where it interacts with the phosphorylated form of IP 3 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 GM 1 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 .

Diseases
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Diseases presenting "ca" symptom

familial hypocalciuric hypercalcemia

gm1 gangliosidosis

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