Regulators of mitochondrial dynamics in cancer

Abstract

Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in physiological conditions and are often deregulated in cancer. Mitochondrial protein homeostasis, transcriptional regulation, and post-translational modification are among processes that govern the control of mitochondrial dynamics. Cancer cells alter mitochondrial dynamics to resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiating and transformation properties including proliferation, migration, and therapeutic resistance. This review focuses on key regulators of mitochondrial dynamics and their role in cancer.

Figure 1. Mitochondrial Dynamics

The double membrane structure of the mitochondrion creates distinct compartments. The mitochondrial outer membrane (MOM) and the mitochondrial inner membrane (MIM) separate the intermembrane space (IMS) from the cytoplasm and the mitochondrial matrix. The electron transport machinery is located in invaginations of the MIM, called cristae. Mitochondrial morphology is determined by a balance between fusion and fission events, mediated by dynamin related GTPases (Drp1, MFN1/2, OPA1). Increased fission events or decreased fusion events results in a fragmented mitochondrial network as observed during mitosis or upon severe stress (e.g. hypoxia, apoptotic insults). Increased fission is necessary to equally distribute mitochondria among daughter cells, and mitochondrial trafficking within the cell. It facilitates mitophagy and is associated with apoptosis. When fusion exceeds fission, elongated mitochondria, often highly interconnected, display increased oxidative capacity, and increased contacts with the endoplasmic reticulum (ER). Increased fusion is observed following nutrient starvation or mild stresses and is considered a homeostatic event to dilute damaged mitochondrial molecules (oxidized lipids, proteins, DNA), escape autophagy and prevent cell death, although fusion reportedly enhances cell death in response to certain stimuli.

Figure 2. Mitochondrial dynamics, quality control and cell fate decision

Dependent on the type and severity of stress, mitochondria undergo either fusion or fission to activate homeostatic pathways or precede cell death. Hyperfused mitochondria relieve mitochondrial stress by complementation of damaged content. They resist mitophagy and increase ATP production to adjust to cellular stresses as nutrient deprivation. ER-mitochondrial Ca²⁺-transfer increased mitochondrial function, while extensive Ca²⁺-overload results in cell death programs. Asymmetric fission segregates mitochondrial content in a polarized manner, resulting in one hyperpolarized mitochondria that is removed from the network by mitophagy, and one hypopolarized, which is reintroduced into the healthy mitochondrial pool. Assymetric fission relies on Drp-1 activity, but the underlying mechanism of polarized segregation of mitochondrial content remains to be determined. Pink1/Parkin-mediated mitophagy is under posttranslational control (proteolytic cleavage, phosphorylation and ubiquitination) and can be counteracted by de-ubiquitinating enzymes or protein-protein interaction between Parkin and antiapoptotic Bcl-2 proteins. Increased Parkin-activity is associated with a shift towards a pro-apoptotic response, as excessive proteasomal degradation of MOM proteins result in mitochondrial membrane disruption and cytochrome c leakage. Parkin-mediated ubiquitination and subsequent degradation of antiapoptotic Mcl-1 increases Bax/Bak-dependent membrane permeabilization and triggers apoptosis.