From cell signalling to cell death: endoplasmic reticulum-mitochondria calcium transfer and its remodelling for cancer cell survival

The tight interplay between endoplasmic reticulum (ER) and mitochondria is a key determinant of cell function and survival through the control of intracellular calcium (Ca2+) signalling. The physical platform for the association between the ER and mitochondria is a domain of the ER called the “mitochondria-associated membranes” (MAMs). MAMs are crucial for highly efficient transmission of Ca2+ from the ER to mitochondria, thus controlling fundamental processes involved in energy production and also determining cell fate by triggering or preventing apoptosis. In particular, we show that: i) despite different roles in cell survival, all three isoforms of the outer mitochondrial membrane protein voltage-dependent anion channels (VDAC) are equivalent in allowing mitochondrial Ca2+ loading upon agonist stimulation, vice versa VDAC1, by selectively interacting with the inositol trisphosphate receptors (IP3Rs) - an interaction that is further strengthened by apoptotic stimuli - is preferentially involved in the transmission of the low-amplitude apoptotic Ca2+ signals to mitochondria, highlighting a non-redundant molecular route for transferring Ca2+ signals to mitochondria in apoptosis; ii) the promyelocytic leukemia (PML) tumor suppressor exerts its extranuclear proapoptotic action by its unexpected and fundamental role at MAMs, where PML was found in protein complexes with the type 3 IP3R, the protein kinase Akt and the phosphatase PP2a, which are essential for Akt- and PP2a-dependent modulation of IP3R phosphorylation and in turn for IP3R-mediated Ca2+ release from ER; iii) the PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor localizes at the ER and MAMs, and ER-localized PTEN is specifically involved in increasing both Ca2+ transfer from the ER to mitochondria and cell sensitivity to Ca2+-mediated apoptosis. The improved knowledge of the functioning of proteins involved in regulating Ca2+ signalling may reveal novel unexplored pharmacological targets, and help in treating cancer as well as other pathologies.