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

doi:10.1016/j.molcel.2009.10.021

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

Vollum Institute

Research output: Contribution to journal › Article › peer-review

254 Scopus citations

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	https://doi.org/10.1016/j.molcel.2009.10.021
State	Published - Nov 13 2009

Funding

We thank K. Sandhoff for critical reading of the manuscript, L. Hendershot for providing the CHO cells overexpressing BiP, and A. Barsoukova for help with pericam experiments. We also thank S. Connell, L. Mann, J. Williams, and S. Frase of the Cell and Tissue Imaging Shared Resource of St. Jude Children's Research Hospital (CRH) for help with confocal and electron microscopy; A.M. Hamilton-Easton and R. Ashmun of the Flow Cytometry Laboratory of St. Jude CRH for FACS analyses; we thank C. Hill for secretarial assistance and A. McArthur for help with editing the manuscript. We gratefully appreciate the donation of GM1 from TRB Pharma, Brazil. A.d'A. holds an Endowed Chair in Genetics and Gene Therapy from the Jeweler's Charity Fund. This work was supported in part by National Institutes of Health (NIH) grants DK052025 and GM060905, the NIH Cancer Center Support Grant CA021765, the Lysosomal Storage Disease Consortium, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude CRH.

Funders	Funder number
Lysosomal Storage Disease Consortium
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	CA021765, GM060905, DK052025
National Institute of Neurological Disorders and Stroke	R01NS065951
Assisi Foundation of Memphis
St. Jude Medical
American Lebanese Syrian Associated Charities

Keywords

CELLCYCLE
HUMDISEASE
SIGNALING

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2009.10.021

Cite this

@article{86fd7e806a4d4968aaff08a4b29a7797,

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

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.",

keywords = "CELLCYCLE, HUMDISEASE, SIGNALING",

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

note = "Funding Information: We thank K. Sandhoff for critical reading of the manuscript, L. Hendershot for providing the CHO cells overexpressing BiP, and A. Barsoukova for help with pericam experiments. We also thank S. Connell, L. Mann, J. Williams, and S. Frase of the Cell and Tissue Imaging Shared Resource of St. Jude Children's Research Hospital (CRH) for help with confocal and electron microscopy; A.M. Hamilton-Easton and R. Ashmun of the Flow Cytometry Laboratory of St. Jude CRH for FACS analyses; we thank C. Hill for secretarial assistance and A. McArthur for help with editing the manuscript. We gratefully appreciate the donation of GM1 from TRB Pharma, Brazil. A.d'A. holds an Endowed Chair in Genetics and Gene Therapy from the Jeweler's Charity Fund. This work was supported in part by National Institutes of Health (NIH) grants DK052025 and GM060905, the NIH Cancer Center Support Grant CA021765, the Lysosomal Storage Disease Consortium, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude CRH. ",

year = "2009",

month = nov,

day = "13",

doi = "10.1016/j.molcel.2009.10.021",

language = "English (US)",

volume = "36",

pages = "500--511",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

}

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

N1 - Funding Information: We thank K. Sandhoff for critical reading of the manuscript, L. Hendershot for providing the CHO cells overexpressing BiP, and A. Barsoukova for help with pericam experiments. We also thank S. Connell, L. Mann, J. Williams, and S. Frase of the Cell and Tissue Imaging Shared Resource of St. Jude Children's Research Hospital (CRH) for help with confocal and electron microscopy; A.M. Hamilton-Easton and R. Ashmun of the Flow Cytometry Laboratory of St. Jude CRH for FACS analyses; we thank C. Hill for secretarial assistance and A. McArthur for help with editing the manuscript. We gratefully appreciate the donation of GM1 from TRB Pharma, Brazil. A.d'A. holds an Endowed Chair in Genetics and Gene Therapy from the Jeweler's Charity Fund. This work was supported in part by National Institutes of Health (NIH) grants DK052025 and GM060905, the NIH Cancer Center Support Grant CA021765, the Lysosomal Storage Disease Consortium, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude CRH.

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 - https://www.scopus.com/pages/publications/70449088871

UR - https://www.scopus.com/pages/publications/70449088871#tab=citedBy

U2 - 10.1016/j.molcel.2009.10.021

DO - 10.1016/j.molcel.2009.10.021

M3 - Article

C2 - 19917257

AN - SCOPUS:70449088871

SN - 1097-2765

VL - 36

SP - 500

EP - 511

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -