GM1-Ganglioside Accumulation at the Mitochondria-Associated ER Membranes Links ER Stress to Ca2+-Dependent Mitochondrial Apoptosis

Renata Sano, Ida Annunziata, Annette Patterson, Simon Moshiach, Elida Gomero, Joseph Opferman, Michael Forte, Alessandra d'Azzo

Research output: Contribution to journalArticle

148 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)500-511
Number of pages12
JournalMolecular Cell
Volume36
Issue number3
DOIs
StatePublished - Nov 13 2009

Fingerprint

G(M1) Ganglioside
Mitochondria
Apoptosis
Membranes
Organelles
GM1 Gangliosidosis
Lysosomal Storage Diseases
Inositol 1,4,5-Trisphosphate Receptors
Glycosphingolipids
Mitochondrial Membranes
Endoplasmic Reticulum

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 journalArticle

Sano, Renata ; Annunziata, Ida ; Patterson, Annette ; Moshiach, Simon ; Gomero, Elida ; Opferman, Joseph ; Forte, Michael ; d'Azzo, Alessandra. / GM1-Ganglioside Accumulation at the Mitochondria-Associated ER Membranes Links ER Stress to Ca2+-Dependent Mitochondrial Apoptosis. In: Molecular Cell. 2009 ; Vol. 36, No. 3. pp. 500-511.
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