Abstract
Mitochondria-associated ER membranes, or MAMs, define the sites of endoplasmic reticulum/mitochondria juxtaposition that control Ca2+ 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. Ca2+ depleted from the ER is then taken up by the mitochondria, leading to Ca2+ 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 Ca2+ diffusion between the ER and the mitochondria. We propose a new mechanism of Ca2+-mediated apoptotic signaling whereby GM1 accumulation at the GEMs alters Ca2+ dynamics and acts as a molecular effector of both ER stress-induced and mitochondria-mediated apoptosis of neuronal cells.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 500-511 |
| Number of pages | 12 |
| Journal | Molecular Cell |
| Volume | 36 |
| Issue number | 3 |
| DOIs | |
| State | Published - Nov 13 2009 |
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Keywords
- CELLCYCLE
- HUMDISEASE
- SIGNALING
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
GM1-Ganglioside Accumulation at the Mitochondria-Associated ER Membranes Links ER Stress to Ca2+-Dependent Mitochondrial Apoptosis. / Sano, Renata; Annunziata, Ida; Patterson, Annette; Moshiach, Simon; Gomero, Elida; Opferman, Joseph; Forte, Michael; d'Azzo, Alessandra.
In: Molecular Cell, Vol. 36, No. 3, 13.11.2009, p. 500-511.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GM1-Ganglioside Accumulation at the Mitochondria-Associated ER Membranes Links ER Stress to Ca2+-Dependent Mitochondrial Apoptosis
AU - Sano, Renata
AU - Annunziata, Ida
AU - Patterson, Annette
AU - Moshiach, Simon
AU - Gomero, Elida
AU - Opferman, Joseph
AU - Forte, Michael
AU - d'Azzo, Alessandra
PY - 2009/11/13
Y1 - 2009/11/13
N2 - Mitochondria-associated ER membranes, or MAMs, define the sites of endoplasmic reticulum/mitochondria juxtaposition that control Ca2+ 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. Ca2+ depleted from the ER is then taken up by the mitochondria, leading to Ca2+ 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 Ca2+ diffusion between the ER and the mitochondria. We propose a new mechanism of Ca2+-mediated apoptotic signaling whereby GM1 accumulation at the GEMs alters Ca2+ dynamics and acts as a molecular effector of both ER stress-induced and mitochondria-mediated apoptosis of neuronal cells.
AB - Mitochondria-associated ER membranes, or MAMs, define the sites of endoplasmic reticulum/mitochondria juxtaposition that control Ca2+ 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. Ca2+ depleted from the ER is then taken up by the mitochondria, leading to Ca2+ 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 Ca2+ diffusion between the ER and the mitochondria. We propose a new mechanism of Ca2+-mediated apoptotic signaling whereby GM1 accumulation at the GEMs alters Ca2+ dynamics and acts as a molecular effector of both ER stress-induced and mitochondria-mediated apoptosis of neuronal cells.
KW - CELLCYCLE
KW - HUMDISEASE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=70449088871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70449088871&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2009.10.021
DO - 10.1016/j.molcel.2009.10.021
M3 - Article
C2 - 19917257
AN - SCOPUS:70449088871
VL - 36
SP - 500
EP - 511
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -