Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis

Abstract

Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.

Keywords: contact sites; mitochondria; signaling.

Figure 1

Cancer-relevant interactions between mitochondria and the ER at mito–ER contact sites (MERCs). Calcium transfer from the ER to mitochondria through the IP3R–GRP75–VDAC complex modulates mitochondrial energy metabolism and apoptosis induction, and is regulated by post-translational modifications of IP3R, ROS and associations with proteins such as TG2 and BRCA1. Further, proteins such as IRE1α and the Sig1R-BiP complex can interfere with the calcium transfer. Mitochondrial ATP, on the other hand, is important for the correct functioning of SERCA, and thus ER calcium homeostasis. These mechanisms influence, amongst others, cancer cell proliferation, invasion, cell death and mitochondrial dynamics. In addition to calcium, lipid homeostasis is also regulated at MERCs. MFN2 is important for the transfer of phosphatidylserine (PS) from the ER to mitochondria, where it is converted to phosphatidylethanolammine (PE), while the MAM-resident protein ACAT1 converts cholesterol to ceramide, a sphingolipid often abundantly found in cancer. Impaired lipid homeostasis has been associated with different kinds of tumors, such as liver, breast, pancreatic and colon cancers. For abbreviations, please refer to the text. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2

Interplay between mitochondria and Wnt signaling. Mitochondria can modulate intracellular signaling in different ways. ER stress induced by hypoxia or reduced ATP production in mitochondria leads to a decrease in β-catenin stability and a subsequent reduction in Wnt signaling. On the other hand, the loss of mitochondrial membrane potential can induce the translocation of PGAM5 into the cytosol, where it promotes β-catenin stability. TFAM, a mitochondrial transcription factor, is also thought to contribute to the complex regulation of Wnt signaling by mitochondria. All these events are important factors that allow a dynamic regulation of intracellular signaling. For further details, please refer to the text. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 3

Signaling at mitochondria–lysosome contact sites. GTP-bound Rab7 is important for the tethering of the two organelles and also acts as a docking site for FYCO1 and RILP, which are responsible for the anterograde and retrograde transport of lysosomes among microtubules. The GTP-ase activating protein TBC1D15 is recruited by FIS1 and promotes GTP hydrolysis, leading to an untethering of mitochondria and lysosomes. FIS1 also recruits Drp1, important for mitochondrial fission. MLN64, a presumptive tether protein, contributes to the exchange of iron and cholesterol (chol.). Microfusions of the membranes during hypoxia bring the asparagine endopeptidase (AEP) into close proximity with VDAC, which could protect mitochondria from mitophagy and increase survival by cleaving the C-terminus of the channel. Finally, TRPML1 releases calcium from lysosomes at mitochondria–lysosome contact sites. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 4

Mitochondria–peroxisome contact sites. At these contact sites, enoyl-CoA isomerase 2 (ECI2) is the only physical tethering complex identified to date. The two organelles are thought to communicate with each other also through vesicles, ROS and lipids. Indeed, peroxisomes are important for ROS clearance and β-oxidation of fatty acids. Please refer to the text for further details. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.