"The Loss of Golden Touch": Mitochondria-Organelle Interactions, Metabolism, and Cancer

Abstract

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells' biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.

Keywords: cancer; metabolism; mitochondria; subcellular organelles.

Figure 1

Mitochondrial fission is mainly mediated by DRP1 and FIS1 proteins, associated with increased aerobic glycolysis. This peculiar metabolic asset is typical of tumor cells to support their metabolic demands and their survival. On the other hand, elongation of mitochondria is a two-step event mediated by MFN proteins and OPA1. MFN1 and MFN2 participate in outer mitochondria membrane fusion, while one of OPA1 isoforms (L-OPA1) promotes IMM fusion. Conversely, another OPA1 isoform (S-OPA1) mediates to the opposite trend.

Figure 2

Main mechanisms involved in MAMs development and their role in tumor cell progression. (A). Calcium homeostasis is crucial to promote cell survival. A reduced flow of Ca²⁺ into mitochondria blunts Oxphos activity, thus, reducing ATP production. Moreover, Ca²⁺ induces the glycolytic pathway (Warburg effect), which eventually support cancer cells’ survival and proliferation. (B) Mitochondria fusion and fission programs are strictly controlled to be balanced in a physiological condition. However, during cancer progression, ER mediates mitochondria fission and shifts the equilibrium towards the fragmentation process. DRP1 and MFN2 are the main proteins involved in this context—the former enhances fission while the latter regulates mitochondrial fusion. (C) Tumor cells’ survival depends on the ER-mitochondria distance. Apoptosis happens as a consequence of their proximity, while a greater distance is associated with cell survival, as shown for Tpm, Nogo-B/Reticulon, and FATE1 proteins. (D) ER-mitochondrion tethering alters mitochondrial lipid composition. Specifically, their binding increases cholesterol levels, boosting up aerobic glycolysis and reducing Oxphos activity.

Figure 3

Membrane rearrangement is a pre-requisite for filopodium maturation, cancer cell migration, and metastasis. Different compounds can act on actin reorganization; for example, E2-treated cells display fewer protrusions and more cortical actin bundles, thus, blocking tumor cell migration. ROCK inhibitor (Y27623) causes a decrease in cortical actin bundles and concomitantly enhances protrusive activity, promoting cell migration and metastasis. Actin reorganization is also mediated by PRL, which controls moesin and FAK proteins, both involved in pseudopodia formation and cell migration.