ER-Mitochondria contact sites: A new regulator of cellular calcium flux comes into play

Abstract

Endoplasmic reticulum (ER)-mitochondria membrane contacts are hotspots for calcium signaling. In this issue, Raturi et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512077) show that the thioredoxin TMX1 inhibits the calcium pump SERCA2b at ER-mitochondria contact sites, thereby affecting ER-mitochondrial calcium transfer and mitochondrial bioenergetics.

Figure 1.

The impact of TMX1 on Ca²⁺ signaling at the ER–mitochondria interface. The physical linkage of the ER-located IP3R channels and outer mitochondrial membrane–located VDAC1 channels establish “quasi-synaptic” transfer of Ca²⁺ from the ER to the mitochondria, where Ca²⁺ is imported into the mitochondrial matrix via the mitochondrial Ca²⁺ uniporter (MCU) complex. Mitochondrial Ca²⁺ transients are essential to stimulate ATP synthesis through the electron transport chain, whereas mitochondrial Ca²⁺ overload triggers apoptosis. Release of Ca²⁺ from the ER toward mitochondria is controlled by different factors, including redox-sensitive chaperones within the ER lumen, such as Ero1α, ERp44, GRP78/BiP, and Sigma1 receptor. Mitochondrial Ca²⁺ transients are able to trigger H₂O₂ release from mitochondrial cristae, stimulating ER Ca²⁺-release events. In most cells, ER Ca²⁺ uptake is mediated by SERCA2b. The activity of SERCA2b is tightly regulated, and ER Ca²⁺ loading activity affects ER–mitochondrial Ca²⁺ flux. CNX is targeted to the MAM by palmitoylation and phosphofurin acidic cluster sorting protein 2 (PACS2) and stimulates SERCA2b activity. Similarly, SEPN1 positively modulates ER Ca²⁺ uptake through SERCA2b. Raturi et al. (2016) add TMX1 to the SERCA2b regulatory network: TMX1 is targeted to ER–mitochondria contact sites through palmitoylation. TMX1–SERCA2b complex formation is enhanced by ROS and is antagonized by CNX. TMX1 binds SERCA2b, causing its inhibition. (A) In conditions of high TMX1 expression, TMX1 causes strong SERCA2b inhibition. This leads to an augmented Ca²⁺ flux to the mitochondria after IP₃-dependent stimulation of the cells. (B) In condition of low TMX1 expression, e.g., in cancer cells, ER Ca²⁺ uptake rates are increased and ER–mitochondrial contacts are decreased. The increase in SERCA2b activity together with the increase in overall distance between ER and mitochondria, which may impact IP3R–GRP75­–VDAC1 complex formation, limits ER–mitochondrial Ca²⁺ transfer and mitochondrial TCA cycling. This mechanism could contribute to the Warburg effect in cancer cells.