Role of Mitochondria-Associated ER Membranes in Calcium Regulation in Cancer-Specific Settings

Abstract

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term “cancer” denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective.

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

“…These findings indicate a pro-survival role of basal IP 3 /Ca 2+ signaling, but further work is needed to document this in other B-cell cancers and lymphoproliferative malignancies. Nevertheless, these results converge with findings obtained in solid tumors, showing that tumorigenic, but not non-tumorigenic, cells depend on basal IP 3 R function for their survival [34][35][36]. In these cancer models, IP 3 Rs provide a constitutive ER-mitochondrial Ca 2+ flux to drive mitochondrial metabolism and the production of mitochondrial substrates needed for nucleotide synthesis critical for cancer cell proliferation.…”

“…In these cancer models, IP 3 Rs provide a constitutive ER-mitochondrial Ca 2+ flux to drive mitochondrial metabolism and the production of mitochondrial substrates needed for nucleotide synthesis critical for cancer cell proliferation. Normal cells are less dependent on IP 3 Rs for their survival, as they can tune down proliferation to accommodate the compromised mitochondrial bioenergetics [34][35][36]. However, further research is needed to determine whether constitutive IP 3 signaling and basal IP 3 R function are both essential for B-cell cancer cell survival by mediating ER-mitochondrial Ca 2+ fluxes that sustain mitochondrial metabolism, thereby accounting for U73122-induced cell death [34,35].…”

Endoplasmic reticulum–mitochondria crosstalk: from junction to function across neurological disorders

“…). Out of the three isoforms of IP3Rs, type 3 isoform is strongly enriched at the MAMs as compared with type 1 and 2 isoforms . Silencing of IP3R type 3 receptors in Chinese hamster ovary (CHO) cells markedly decreased the mitochondrial Ca 2+ concentration and reduced apoptosis .…”

Commonalities and differences in the Oxidative Phosphorylation of Mitochondria and Neuronal Membranes

“…This could be explained considering that the OxPhos machinery is organized in a "supercomplex" (Wittig et al 2006;Lenaz and Genova 2009), which may be easily transferred from mitochondria to other membranous structures Bartolucci et al 2015). On the other hand, mitochondria are dynamic organelle, able to fuse with other cellular compartments, such as the endoplasmic (de Brito and Scorrano 2010;Raturi and Simmen 2013), playing a pivotal role in the control of cell survival (Doghman-Bouguerra and Lalli 2019), calcium flux (Morciano et al 2018), lipid metabolism (Flis and Daum 2013), and the entire energy metabolism (Rieusset 2018;Tubbs and Rieusset 2017;Lee and Min 2018;Marchi et al 2014). A myelin that store energy opens up exciting prospects in the study of sleep, having been shown that sleep has been shown to lead to an increase in brain ATP (Dworak et al 2010).…”