Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

Abstract

The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca 2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.Keywords: endoplasmic reticulum, mitochondria, mitochondria-associated membranes, Ca 2+ signaling, eR stress, autophagy, inflammasome, cancer cell Abbreviations: AA, arachidonoyl; ATF4, activating transcription factor 4; ATG, autophagy-related gene; Bcl-2, B-cell lymphoma 2; Bcl-XL, B-cell lymphoma-extra large; BECN1, Beclin-1; Ca 2 + , calcium; Cav-1, caveolin-1; CL, cardiolipin; CNX, calnexin; cyt c, cytochrome c; Drp1, dynamin-related protein 1; ER, endoplasmic reticulum; Grp78, glucose-regulated protein 78; HK2, hexokinase 2; IL-1β, interleukin 1β; IL-18, interleukin 18; IP3, inositol trisphosphate; IP3R, inositol 1, 4, 5-trisphosphate receptor; IP3R3, inositol 1, 4, 5-trisphosphate receptor 3; IRE1, inositol requiring enzyme 1; MAMs, mitochondria-associated membranes; MAVS, mitochondrial antiviral-signaling protein; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mTORC2, mammalian target of rapamycin 2; NLRP3, NOD-like receptor family 3; OMM, outer mitochondrial membrane; ORP5, oxysterol-binding protein (OSBP)-related protein (ORP) 5; ORP8, oxysterol-binding protein (OSBP)-related protein (ORP) 8; PA, phosphatidic acid; PACS-2, phosphofurin acidic cluster sorting protein 2; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PERK, double stranded RNA-activated protein kinase (PKR)-like ER kinase; PI, phosphatidylinositol; PM, plasma membrane; PML, promyelocytic leukemia; PP2A, protein phosphatase 2A; PS, phosphatidylserine; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTPIP51, protein tyrosine phosphatase-interacting protein 51; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca 2+ ATPase; SERCA2b, sarco/endoplasmic reticulum Ca 2 + ATPase isoform 2b; Sigma1 receptor, S1R; StAR, cholesterol transport steroidogenic acute regula...

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

“…CORE regulates ER-mitochondrial interactions, and was first identified in 2016 as an intrinsic mechanism for preventing proteotoxicity 12,[54][55][56] . Mitochondrial-associated membranes (MAMs) mediate interactions between mitochondria and ER in proximal tubule cells, and the protein resorption requirements of the proximal tubule likely necessitate this inter-organelle relationship 43 .…”

Targeted OMA1 therapies for cancer

“…Mitochondria are also in contact with the ER through MFN2 and other proteins enriched in mitochondria‐associated ER membranes (MAM) . MAMs are involved in the biogenesis of mitochondria, calcium exchange, autophagy, and stress‐signaling through the unfolded protein response and other pathways . Alterations of the mitochondria‐ER contact sites have been documented in cancer cells .…”

“…In addition, mitochondria also redistribute from a perinuclear to a more cortical localization . And it is tempting to speculate that the reduced number of mitochondria‐ER contact sites due to the more cortical mitochondrial localization could provide a selective advantage for cancer cells by influencing threshold levels for apoptosis . In addition, replicating cells undergo cycles of mitochondrial fission and fusion that correlate with the cell cycle.…”

“…152,153 MAMs are involved in the biogenesis of mitochondria, calcium exchange, autophagy, and stresssignaling through the unfolded protein response and other pathways. [154][155][156] Alterations of the mitochondria-ER contact sites have been documented in cancer cells. 157 In addition, mitochondria also redistribute from a perinuclear to a more cortical localization.…”

“…135,158 And it is tempting to speculate that the reduced number of mitochondria-ER contact sites due to the more cortical mitochondrial localization could provide a selective advantage for cancer cells by influencing threshold levels for apoptosis. 156 In addition, replicating cells undergo cycles of mitochondrial fission and fusion that correlate with the cell cycle. Mitochondria fragment during cell division and adapt an increasingly fused state during the growth phase of the cell cycle.…”