Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism

Abstract

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when ‘parked’, mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

“…The reduction of both proteins could exacerbate the phenotype of mitochondrial Ca 2+ -overload. By evaluating oligomeric dynamic changes using SEC, we found that the OMM channel, VDAC, and MCU's gating regulator, MICU1, showed a matching elution pattern with MCU, and the treatment of Fe 2+ shifted all 3 proteins to the similar earlier fractions of higher order oligomers, which coincided with the elution peak of MIC60, a core structural protein at the crista junctions and contact sites (Zerbes et al, 2012), and IP3R1, the major ER Ca 2+ -channel that delivers Ca 2+ to the OMM (Katona et al, 2022) (Figure 5A, C). These data are consistent with VDAC, MICU1, and MCU being associated in the same super-complexes and suggest a possible spatial reorganization of the MCU super-complexes upon iron elevation, thus allowing easier access to ER Ca 2+ supply.…”

ER network heterogeneity guides diffusive transport and kinetics

“…Given that calcium homeostasis and signaling is one of the key functional roles of the ER, heterogeneous transport could thus provide an important link between physical structure and biological function. Furthermore, it would be interesting to explore whether contacts between the peripheral ER and other cellular structures, such as mitochondria, tend to preferentially occur at highly connected regions, which may facilitate the delivery of lipids or ions across these contacts (71)(72)(73).…”

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

“…Furthermore, the dogma that the IP 3 R-GRP75-VDAC tripartite complex forms a funnel through which Ca 2+ is exchanged from the ER to the mitochondria, requires closer scrutiny. Firstly, there is evidence that other binding partners can interact with IP 3 R to form ERMCS where Ca 2+ exchange occurs, as is the case for IP 3 R interacting with the AKAP1 transmembrane domain or TOM70 on the mitochondrial membrane (Katona et al, 2022). Although it is important to note that TOM70 has been shown to interact directly with the IP 3 R-GRP75-VDAC complex (SECTION 3.3); therefore, TOM70 may well be a coincident reporter of the same IP 3 R-GRP75-VDAC junctions.…”

“…Recent evidence suggests that IP 3 Rs may play a structural role in ERMCS formation which is independent of their ability to deliver Ca 2+ from the ER for mitochondrial uptake via the MCU. HEK293 cells are reported to show limited ER–mitochondrial Ca 2+ transfer, but tight IP 3 R-dependent ERMCS (Katona et al, 2022). HEK293 cells lacking IP 3 R showed fewer regions of close apposition (<20 nm) between the ER and mitochondria and re-expression of IP 3 Rs including a non-Ca 2+ conducting mutant in HEK293 cells rescued the contacts between the ER and mitochondria (Katona et al, 2022).…”

“…HEK293 cells are reported to show limited ER–mitochondrial Ca 2+ transfer, but tight IP 3 R-dependent ERMCS (Katona et al, 2022). HEK293 cells lacking IP 3 R showed fewer regions of close apposition (<20 nm) between the ER and mitochondria and re-expression of IP 3 Rs including a non-Ca 2+ conducting mutant in HEK293 cells rescued the contacts between the ER and mitochondria (Katona et al, 2022). Recruitment of mobile IP 3 R at ER–mitochondrial contacts has been shown to license the IP 3 Rs to rapidly deliver Ca 2+ to the mitochondria and increase the activity of mitochondrial Ca 2+ -sensitive dehydrogenases (Katona et al, 2022).…”