Cancer cells are critically dependent on ER–mitochondria Ca2+ flux that regulates their bioenergetics. Here, Raturi et al. identify the ER oxidoreductase TMX1 as a thiol-dependent regulator of this intracellular signaling mechanism within cancer cells.
The past decade has seen dramatic progress in our understanding of membrane contact sites (MCS). Important examples of these are endoplasmic reticulum (ER)-mitochondria contact sites. ER-mitochondria contacts have originally been discovered in mammalian tissue, where they have been designated as mitochondria-associated membranes (MAMs). It is also in this model system, where the first critical MAM proteins have been identified, including MAM tethering regulators such as phospho-furin acidic cluster sorting protein 2 (PACS-2) and mitofusin-2. However, the past decade has seen the discovery of the MAM also in the powerful yeast model system Saccharomyces cerevisiae. This has led to the discovery of novel MAM tethers such as the yeast ER-mitochondria encounter structure (ERMES), absent in the mammalian system, but whose regulators Gem1 and Lam6 are conserved. While MAMs, sometimes referred to as mitochondria-ER contacts (MERCs), regulate lipid metabolism, Ca2+ signaling, bioenergetics, inflammation, autophagy and apoptosis, not all of these functions exist in both systems or operate differently. This biological difference has led to puzzling discrepancies on findings obtained in yeast or mammalian cells at the moment. Our review aims to shed some light onto mechanistic differences between yeast and mammalian MAM and their underlying causes.
Reviewers: This article was reviewed by Paola Pizzo (nominated by Luca Pellegrini), Maya Schuldiner and György Szabadkai (nominated by Luca Pellegrini).
The discovery of proteins regulating ER-mitochondria tethering including phosphofurin acidic cluster sorting protein 2 (PACS-2) and mitofusin-2 has pushed contact sites between the endoplasmic reticulum (ER) and mitochondria into the spotlight of cell biology. While the field is developing rapidly and controversies have come and gone multiple times during its history, it is sometimes overlooked that significant research has been done decades ago with the original discovery of these structures in the 1950s and the first characterization of their function (and coining of the term mitochondria-associated membrane, MAM) in 1990. Today, an ever-increasing array of proteins localize to the MAM fraction of the endoplasmic reticulum (ER) to regulate the interaction of this organelle with mitochondria. These mitochondria-ER contacts, sometimes referred to as MERCs, regulate a multitude of biological functions, including lipid metabolism, Ca signaling, bioenergetics, inflammation, autophagy, mitochondrial structure, and apoptosis.
Following the discovery of the mitochondria-associated membrane (MAM) as a hub for lipid metabolism in 1990 and its description as one of the first examples for membrane contact sites at the turn of the century, the past decade has seen the emergence of this structure as a potential regulator of cancer growth and metabolism. The mechanistic basis for this hypothesis is that the MAM accommodates flux of Ca2+ from the endoplasmic reticulum (ER) to mitochondria. This flux then determines mitochondrial ATP production, known to be low in many tumors as part of the Warburg effect. However, low mitochondrial Ca2+ flux also reduces the propensity of tumor cells to undergo apoptosis, another cancer hallmark. Numerous regulators of this flux have been recently identified as MAM proteins. Not surprisingly, many fall into the groups of tumor suppressors and oncogenes. Given the important role that the MAM could play in cancer, it is expected that proteins mediating its formation are particularly implicated in tumorigenesis. Examples for such proteins are mitofusin-2 and phosphofurin acidic cluster sorting protein 2 that likely act as tumor suppressors. This review discusses how these proteins that mediate or regulate ER–mitochondria tethering are (or are not) promoting or inhibiting tumorigenesis. The emerging picture of MAMs in cancer seems to indicate that in addition to the downregulation of mitochondrial Ca2+ import, MAM defects are but one way how cancer cells control mitochondria metabolism and apoptosis.
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