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

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.