Role of Extended-Synaptotagmin 1 (Esyt1) at the ER-mitochondria membrane contact sites

Identification: Janer, Alexandre


Description

Role of Extended-Synaptotagmin 1 (Esyt1) at the ER-mitochondria membrane contact sites
 
Janer A1,2, Straub I1,2, Antonicka H1,2, Daignault K1,2, Prudent J3, Gingras AC4,5, Shoubridge E1,2
1Department of Human Genetics, McGill University, Montreal, QC, Canada
2Montreal Neurological Institute, McGill University, Montreal, QC, Canada
3Medical Research Council, Mitochondrial Biology Unit, Cambridge, UK
4Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
5Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
 
Membrane contacts sites (MCS) between ER and mitochondria play a central role in cell fate, regulating physiological signals and metabolic fluxes, and are implicated in the pathophysiology of several neurodegenerative disorders.
We recently identified SLC25A46, the mammalian orthologue of Ugo1, as a mitochondrial outer membrane protein that interacts both with MFN2, OPA1, and the MICOS complex in mitochondria and the EMC complex at the ER, coupling lipid flux between the ER and mitochondria, directly at outer/inner mitochondrial membrane contacts.
 
In the present study, BioID analysis, a proximity labeling technique enabling the detection of protein-protein interactions in living cells, demonstrated an interaction of SLC25A46 with the ER protein Esyt1 (Extend-Synaptotagmin 1). Esyt1 is an SMP domain protein known to tether the ER to the plasma membrane (PM), under the regulation of both cytosolic Ca2+ and PM PI(4,5)P2, and to support the transfer of lipids between the 2 membranes. The presence of Esyt1 at ER-mitochondria MCS was confirmed by cellular fractionation and immunofluorescence colocalisation analysis. The role of Esyt1 in membrane tethering, lipid transfer, calcium homeostasis, as well as mitochondrial physiology, is under investigation.
 
We recently identified SLC25A46, the mammalian orthologue of Ugo1, as a mitochondrial outer membrane protein that interacts both with MFN2, OPA1, and the MICOS complex in mitochondria and the EMC complex at the ER, coupling lipid flux between the ER and mitochondria, directly at outer/inner mitochondrial membrane contacts.
In the present study, BioID analysis, a proximity labeling technique enabling the detection of protein-protein interactions in living cells, demonstrated an interaction of SLC25A46 with the ER protein Esyt1 (Extend-Synaptotagmin 1). Esyt1 is an SMP domain protein known to tether the ER to the plasma membrane (PM), under the regulation of both cytosolic Ca2+ and PM PI(4,5)P2, and to support the transfer of lipids between the 2 membranes. The presence of Esyt1 at ER-mitochondria MCS was confirmed by cellular fractionation and immunofluorescence colocalisation analysis. The role of Esyt1 in membrane tethering, lipid transfer, calcium homeostasis, as well as mitochondrial physiology, is under investigation.

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