Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death

Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly of Ca 2+ signaling complexes at the ER/PM compartment

“…Such an arrangement is essential to generate spatially and temporally precise Ca 2+ signals to modulate specific cellular activity at the site where the Ca 2+ signal is evoked (Park et al , ; Ahuja et al , ). It is now clear that compartmentation of cell signaling is achieved by targeting signaling proteins to membrane contact sites (MCSs; Lahiri et al , ; Chung et al , ; Marchi et al , ; Muallem et al , ; Nunes‐Hasler & Demaurex, ). MCSs are formed between the ER and all cellular organelles, including the mitochondria (Marchi et al , ) and the PM (Henne et al , ; Chung et al , ), by tether proteins.…”

Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness

“…Interestingly, FBXL2 activity itself is Ca 2+ dependent, but antagonized by calmodulin [41]. Hence, activation of IP 3 Rs may not only make these channels more susceptible for degradation by increased interaction with FBXL2 but release of Ca 2+ itself through IP 3 Rs may trigger local activation of FBXL2 associated with IP 3 R3 leading to IP 3 R3 degradation. Notably, FBXL2 binding to its substrates (like cyclin D3) was found to occur via canonical calmodulin-binding motif thereby preventing ubiquitination.…”

“…Over the last decade, we learnt that tight contacts and functional connections involving Ca 2+ exchanges between the ER, the main intracellular Ca 2+ -storage organelle, and the mitochondria are pivotal for cell-fate decisions [3,[6][7][8].…”

“…In healthy cells, Ca 2+ signaling is employed for normal cell physiology and survival functions [2]. Yet, when a cell is exposed to toxic stimuli or suffering from enduring cell stress, like irreparable DNA damage, the Ca 2+ -signaling toolbox can be rapidly switched from a "pro-survival" modus into a "pro-death" modus, thereby initiating demise pathways [3]. The highly dynamic nature of Ca 2+ signaling allows cells to swiftly response to stress and damage, preventing the survival of damaged cells and malignant transformation that eventually results in tumor formation.…”

“…Alterations in the expression, activity and regulation of Ca 2+ -transport systems both at the plasma membrane and at organelles like the endoplasmic reticulum (ER) and mitochondria have been implicated in oncogenesis and neoplasia [1,4]. These changes result in aberrant Ca 2+ -signaling events that could favor resistance to cell death, migration or senescence escape [5].Over the last decade, we learnt that tight contacts and functional connections involving Ca 2+ exchanges between the ER, the main intracellular Ca 2+ -storage organelle, and the mitochondria are pivotal for cell-fate decisions [3,[6][7][8].These contact sites contain chaperone-coupled Ca 2+ -flux systems: the IP 3 receptors (IP 3 Rs) at the ER side and the voltage-dependent anion channels (VDACs) at the mitochondrial outer membrane side [9]. These are controlled/exploited by several cellular factors and regulatory proteins, including oncogenes and tumor suppressors [10][11][12].…”