The mitochondrial dynamics in cancer and immune-surveillance

Abstract

A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

“…On the contrary, active Drp1-S616E restores the fragmentation of the mitochondrial network in AICD-induced and FR180204-treated Jurkat cells ( Fig. 4e), which is a prerequisite for MOMP [14]. The latter normally requires Bax/Bak oligomerization on the OMM, in which Bim plays a positive role, too [21].…”

Metabolic Plasticity of Tumor Cell Mitochondria

“…Indeed, a prolonged DRP1 downregulation can inhibit respiration, suggesting that a proper OXPHOS modulation requires a balanced interplay between mitochondrial fission and fusion (189). Thus, it is difficult at present to make mechanistic correlations between mitochondrial dynamics and metabolism and to understand whether changes in the mitochondrial network of cancer cells are priming events or consequences of their metabolic rewiring.…”

“…For instance, even if activation of several oncogenes increases fission, some others, such as Myc, promote mitochondrial fusion (187). Moreover, mitochondrial shape can impact on intramitochondrial Ca 2+ waves (185) and on Ca 2+ fluxes at MAMs (189), thus playing a complex and probably context-dependent role on the metabolic adaptations of tumor cells (see section Mitochondrial Ca 2+ And Metabolic Plasticity).…”

“…Mitochondrial fission is strictly connected to mitophagy, a quality control process that maintains mitochondrial integrity and function through removal of damaged organelles, which must be isolated from the healthy network via DRP1-dependent sequestration (189, 190). Mitophagy is activated by a variety of stresses usually encountered by neoplastic cells, including hypoxia, nutrient deprivation, DNA damage and inflammation, which eventually cause mitochondrial membrane depolarization and decline in respiratory capability (149).…”

“…In cancer, a disruption of the homeostatic equilibrium between mitophagy and mitogenesis occurs (191, 192). It has been proposed that impairment of a correct mitophagy could be advantageous for the early phases of neoplastic growth, contributing to set a novel redox equilibrium, whereas later stages of tumor progression would be favored by mitophagy, as it would protect tumor cells from excessive mitochondrial damage, surge in ROS levels and apoptosis (189). Further work is certainly needed to draw a more complete picture of the functional interplay between mitochondrial fusion and fission, mitophagy and metabolic rewiring of cancer cells.…”