Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

Abstract

Ovarian cancer (OC) represents the main cause of death from gynecological malignancies in western countries. Altered cellular and mitochondrial metabolism are considered hallmarks in cancer disease. Several mitochondrial aspects have been found altered in OC, such as the oxidative phosphorylation system, oxidative stress and mitochondrial dynamics. Mitochondrial dynamics includes cristae remodeling, fusion, and fission processes forming a dynamic mitochondrial network. Alteration of mitochondrial dynamics is associated with metabolic change in tumour development and, in particular, the mitochondrial shaping proteins appear also to be responsible for the chemosensitivity and/or chemoresistance in OC. In this review a focus on the mitochondrial dynamics in OC cells is presented.

Keywords: DRP1; MFN2; OPA1; cAMP/PKA; mitochondria; mitochondrial dynamics; ovarian cancer; prohibitin.

Figure 1

Schematic representation of mitochondrial structures. Mitochondria have a mitochondrial outer membrane (MOM), an intermembrane space, and a mitochondrial inner membrane (MIM). The inner membrane borders the mitochondrial matrix and forms mitochondrial cristae. The enzymes of mitochondrial respiration chain, complexes I, III and IV (CxI, CxIII, CxIV) and ATP synthase (Cx V) are localized in the MIM. The electron transfer through the mitochondrial respiratory complexes is coupled to the proton transfer (H⁺) from the matrix to the intermembrane space generating a mitochondrial membrane potential used for releasing ATP from CxV. Mitochondria complexes I and III generate oxygen reactive species (O₂^.) [30].

Figure 2

Mitochondrial alterations in cancer. Several aspects have been found altered in cancer cells, such as mtDNA mutation, mitochondria-nuclear communication, oxidative stress, cell apoptosis, autophagy, dynamics and calcium overload [38,39,40]. To sustain cell proliferation, the cancer cells acquire the ability to change their metabolism equilibrating both glycolysis and OXPHOS for ATP production [43,44].

Figure 3

Mitochondrial dynamics protein levels in chemosensitivity and chemoresistance of ovarian cancer. Mitochondrial dynamics proteins are involved in chemosensitivity and/or chemoresistance in OC [28]. A pro-fusion equilibrium has been observed in drug-resistant cells associated with increased levels of several mitochondrial shaping proteins such as MFN2, OPA1 PHB2, and phosphorylated DRP1 at serine 637 [119,120,121,122]. On the contrary, a pro-fission equilibrium has been observed in drug-induced cell death associated with increased levels of several mitochondrial shaping proteins such as P53, activated OMA1, DRP1 and phosphorylated DRP1 at serine 616 [123,124,125,126].

Figure 4

Cytosolic cAMP-dependent control of mitochondrial dynamics. Dephosphorylated form of DRP1 at serine 637 localizes in mitochondria forming a ring surrounding mitochondrial outer membrane and promoting fission event. Activation of cAMP cascade promotes the phosphorylation of DRP1 at serine 637, its delocalization in the cytoplasm and thus promoting fusion event. cAMP level is augmented in OC [21]. The expression of catalytic subunit (C) of PKA and increased mRNA of regulatory subunit (R) are correlated with advanced stage and more aggressive ovarian cancer disease [143,144,145,146,147].

Figure 5

Mitochondrial cAMP-dependent control of mitochondrial dynamics. Soluble adenylyl cyclase produces cAMP inside mitochondria. Mitochondrial cAMP determines fusion event by sustaining SIRT3 protein level that, in turn, deacetylates OPA1 inhibiting its degradation from L to S-forms [21]. OPA1 oligomerization at the inner mitochondrial membrane keeping the cristae junctions tight and favors the fusion event. This prevents the release of cytochrome c (Cyt c) making the cells more resistant to apoptosis. Deregulation of OPA1 protein level and proteolytic processes has been found in OC [119].