Regulation of Endoplasmic Reticulum–Mitochondria Ca2+ Transfer and Its Importance for Anti-Cancer Therapies

Abstract

Inter-organelle membrane contact sites are emerging as major sites for the regulation of intracellular Ca2+ concentration and distribution. Here, extracellular stimuli operate on a wide array of channels, pumps, and ion exchangers to redistribute intracellular Ca2+ among several compartments. The resulting highly defined spatial and temporal patterns of Ca2+ movement can be used to elicit specific cellular responses, including cell proliferation, migration, or death. Plasma membrane (PM) also can directly contact mitochondria and endoplasmic reticulum (ER) through caveolae, small invaginations of the PM that ensure inter-organelle contacts, and can contribute to the regulation of numerous cellular functions through scaffolding proteins such as caveolins. PM and ER organize specialized junctions. Here, many components of the receptor-dependent Ca2+ signals are clustered, including the ORAI1-stromal interaction molecule 1 complex. This complex constitutes a primary mechanism for Ca2+ entry into non-excitable cells, modulated by intracellular Ca2+. Several contact sites between the ER and mitochondria, termed mitochondria-associated membranes, show a very complex and specialized structure and host a wide number of proteins that regulate Ca2+ transfer. In this review, we summarize current knowledge of the particular action of several oncogenes and tumor suppressors at these specialized check points and analyze anti-cancer therapies that specifically target Ca2+ flow at the inter-organelle contacts to alter the metabolism and fate of the cancer cell.

Redox signals at theER–mitochondria interface control melanoma progression

“…The role of ER-mitochondria contacts, metabolism, and ROS in cancer ER-mitochondria contacts act as regulators of redox, Ca 2+ , metabolic, and bioenergetic processes; additionally, due to their contribution to multiple aspects of pro-tumorigenic behavior, these organelles pose interesting targets for anti-cancer therapies (Cardenas et al, 2010;Fulda et al, 2010;Clarke et al, 2014;Theodosakis et al, 2014;Schrepfer & Scorrano, 2016;Zong et al, 2016;Kerkhofs et al, 2017;Pedriali et al, 2017). Mitochondrial metabolic switches and ROS production have been proposed to control melanoma drug and oxidative stress resistance in distinct melanoma subpopulations (Haq et al, 2013;Roesch et al, 2013;Vazquez et al, 2013).…”

“…Abnormal reactive oxygen species (ROS) levels in transformed cells can be attributed to changes in organelle dynamics, an inefficient mitochondrial respiratory chain, increased metabolic needs, altered ROS scavenging, and oncogene-induced stress (Weinberg & Chandel, 2009;Sabharwal & Schumacker, 2014;Willems et al, 2015;Idelchik et al, 2017). At the center of it all, ER and mitochondria, via precise contact sites, play the essential role of coordinating redox, but also calcium (Ca 2+ ) and lipid signaling (Elbaz & Schuldiner, 2011;Rowland & Voeltz, 2012;Booth et al, 2016;Pedriali et al, 2017). Accordingly, alterations in organelle structure and inter-organelle contacts can have profound implications for redox signaling and, hence, tumor cell behavior.…”

The Mitochondrial Ca2+ Overload via Voltage-Gated Ca2+ Entry Contributes to an Anti-Melanoma Effect of Diallyl Trisulfide

“…Ca 2+ released from the IP 3 R can easily reach the mitochondrial matrix via the IP 3 R-voltage-dependent anion channel (VDAC1)-mitochondrial Ca 2+ uniporter (MCU) pathway [31,32]. The ER is the primary mechanism for regulating [Ca 2+ ] mit and tethered to mitochondria via a mitochondria-associated membrane; the physical association allows rapid Ca 2+ transport through specified microdomains [33,34]. The IP 3 R physically links to VDAC1 on the outer mitochondrial membrane and transports Ca 2+ into the mitochondrial matrix [35,36].…”

Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness

“…Tuned ER-mitochondrial Ca 2+ transfer is therefore key to cells' response to pro-apoptotic stimuli: the failure of which results in cell death resistance, as often observed in cancer cells [15,16]. In fact, the efficacy of chemotherapeutic agents and photodynamic therapy depends on the ability of these agents to elicit ER-mitochondrial Ca 2+ exchanges [15]. In the context of apoptosis, previous work proposed unique roles for the type 3 IP 3 R isoform (IP 3 R3) [17] and type 1 VDAC isoform (VDAC1) [18] even though other IP 3 R isoforms can contribute to the initiation of cell death programs [19,20].…”

“…Yet, continued elevated ER-mitochondrial Ca 2+ transfers result in loss of mitochondrial membrane integrity and release of apoptogenic factors [14]. Tuned ER-mitochondrial Ca 2+ transfer is therefore key to cells' response to pro-apoptotic stimuli: the failure of which results in cell death resistance, as often observed in cancer cells [15,16]. In fact, the efficacy of chemotherapeutic agents and photodynamic therapy depends on the ability of these agents to elicit ER-mitochondrial Ca 2+ exchanges [15].…”