@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",
}