Cancer: Untethering Mitochondria from the Endoplasmic Reticulum?

Abstract

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.

Keywords: metabolism; mitochondria-associated membrane; mitochondria-endoplasmic reticulum contacts; mitofusin-2; oncoprotein; tumor suppressor.

Figure 1

Description of key evidence on the role of mitochondria-associated membrane (MAM) tethering factors as tumor suppressors or oncoproteins.

Figure 2

Tumor suppressors (green) and oncoproteins (red) of the mitochondria-associated membrane grouped according to their demonstrated (dark shaded) or suspected role in cancer (light shaded). In the middle, known mammalian tethering regulators or protein complexes, whose role in cancer is ambiguous or unclear.