IP₃R at ER-Mitochondrial Contact Sites: Beyond the IP₃R-GRP75-VDAC1 Ca²⁺ Funnel

Abstract

Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca2+ homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca2+ transfer unit at ERMCS. These are often reported to form a Ca2+ funnel that fuels the mitochondrial low-affinity Ca2+ uptake system. We assess the available evidence on the IP3R subtype selectivity at the ERMCS and consider if IP3Rs have other roles at the ERMCS beyond providing Ca2+. Growing evidence suggests that all three IP3R subtypes can localise and regulate Ca2+ signalling at ERMCS. Furthermore, IP3Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca2+ at these sites. Evidence that various binding partners regulate the assembly and Ca2+ transfer at ERMCS populated by IP3R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca2+ microdomain that is required to fuel mitochondrial Ca2+ uptake.

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“…Similarly, AX also possessed significant intermolecular interaction with these crucial amino acids, indicating the great potential to inhibit channel activity. Certainly, mitochondrial Ca 2+ uptake also depends on VDAC1, which is responsible for the transport of Ca 2+ between cytoplasm and matrix and plays a fundamental role in Ca 2+ homeostasis. , Moreover, VDAC1 triggers mitochondria-mediated apoptosis in the form of oligomerization and induces mitochondria dysfunction. , It has been proved that VDAC1 exists in different oligomer states including monomers, dimers, trimers, tetramers, hexamers, and higher-order oligomers, of which the vital contact site in dimeric VDAC1 involves β-strands 1, 2, and 19. In this study, although the protein expression level of VDAC1 was not significantly affected by AX, the molecular docking results showed that AX was able to act on VDAC1 oligomerization by interacting with the key domain of VDAC1 through hydrophobic interactions and hydrogen bonding.…”

“…Certainly, mitochondrial Ca 2+ uptake also depends on VDAC1, which is responsible for the transport of Ca 2+ between cytoplasm and matrix and plays a fundamental role in Ca 2+ homeostasis. 76,77 Moreover, VDAC1 triggers mitochondria-mediated apoptosis in the form of oligomerization and induces mitochondria dysfunction. 78,79 It has been proved that VDAC1 exists in different oligomer states including monomers, dimers, trimers, tetramers, hexamers, and higher-order oligomers, 80 of which the vital contact site in dimeric VDAC1 involves β-strands 1, 2, and 19.…”

“…Certainly, mitochondrial Ca 2+ uptake also depends on VDAC1, which is responsible for the transport of Ca 2+ between cytoplasm and matrix and plays a fundamental role in Ca 2+ homeostasis. 76,77 Moreover, VDAC1 triggers…”