Introduction

The past decade has witnessed an explosion of knowledge regarding how mitochondrial shape and dynamics impact mitochondrial function and their role in several diseases including cancer.

Mitochondrial shape can shift between small, fragmented units and larger networks of elongated mitochondria by means of coordinated fission and fusion processes [1]. Fusion is mediated by mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) proteins in the outer mitochondrial membrane and by optic atrophy 1 (Opa1) protein in the inner mitochondrial membrane. Fission is mediated by cytosolic dynamin related protein 1 (Drp1) and mitochondrial fission1 protein (Fis1) [1]. Mfn2 is also present in the endoplasmic reticulum (ER) and controls ER morphology and it’s tethering to mitochondria [2].

Mitochondrial dynamics is highly integrated with mitochondrial autophagy (mitophagy), with which it plays a role in regulating mitochondrial quality control. Upon fission, mitochondria can be segregated into polarized and depolarized daughter mitochondria. While polarized daughter mitochondria can undergo fusion, depolarized mitochondria are targeted by mitophagic proteins to degradation [3,4]. Mitophagy promotes turnover of dysfunctional mitochondria that would otherwise hamper the cell homeostasis [5,6].

It has been reported that Mfn2 depletion induces mitochondrial dysfunction [7-10] leading to a decrease of: 1) mitochondrial membrane potential; 2) cellular oxygen consumption; 3) oxidation of glucose, pyruvate, and fatty acids; 5) expression of mitochondrial respiratory complexes subunits with consequent decrease in their enzymatic activity.

Mfn2 is also involved in cell cycle [11], cell proliferation [12]and in apoptosis [13]. Mfn2 overexpression increases the mitochondrial Bax/Bcl-2 ratio thus resulting into a pro-apoptotic effect [13] and depletion of DRP1 causes increased apoptosis in human colon cancer cells [14]. Altered mitochondrial dynamics including a reduced Mfn2 expression were therefore expected in cancer cells; as a matter of fact, Mfn2 expression has been found to be significantly lower in bladder cancer, hepatocellular carcinoma, endometrial cancer and breast cancer than in nearby non-neoplastic tissues [15-18].

In breast cancer patients reduced Mfn2 expression is also associated with poor prognosis; moreover, Mfn2 knockout promotes cell viability, colony formation, and invasion of cancer cells in vitro and in vivo through inhibition of mTORC2/Akt signaling [18].

Patients with hepatocellular carcinoma (HCC) frequently show loss of heterozygosity in the Mfn2 gene [19] and a significant correlation between reduced Mfn2 expression and poorer prognosis [20]. Conversely, Mfn2 overexpression induces in hepatocellular carcinoma cells apoptosis, reduced mitochondrial membrane potential (ΔΨm), reduced endoplasmic reticulum (ER) calcium ion Ca²⁺ concentrations, and elevated intracellular reactive oxygen species (ROS) and mitochondrial Ca²⁺ concentrations [20]. It was also demonstrated that Mfn2 is repressed by microRNA miR-761, which was found to be upregulated in hepatocellular carcinoma, and that the inhibitor of miR-761 repressed tumor growth and metastasis both in vivo and in vitro by upregulating Mfn2 [21].

Finally in bladder cancer, Mfn2 overexpression was found to inhibit cell proliferation by arresting the transition of the cell cycle from the G1 to S phase, and to induce apoptosis by upregulating active caspase-3and increasing cleavage of poly (ADP-ribose) polymerase PARP [15]. Mfn2 therefore seems to be a potential tumor suppressor gene that promotes apoptosis and inhibits the proliferation of cancer cells; this makes Mfn2 a promising therapeutic target. Unfortunately, the finding that other cancers exhibit Mfn2 overexpression has cooled down some enthusiasm. In patients with lung cancer Mfn2 was overexpressed ad its knockdown interrupted cell cycle distribution, inhibited cell proliferation and cell invasion [22]. Similarly, in patients with gastric cancer an overexpression of Mfn2 was found to be positively associated with depth of invasion, stage and vascular invasion, resulting in iferation and invasion [significantly lower disease-free survival rate; moreover, Mfn2 knockdown suppressed cell pro [23]. The role of Mfn2 seems to be controversial in gastric cancer since in a previous study a decrease of Mfn2 expression was reported in tumor tissue than in nearby non-neoplastic [24].

A potential explanation for this paradoxical effect of Mfn2 in different cancer types has come out from microarray analysis showing that Mfn2 knockdown has opposite impact on different oncogenes such as RAP1A, RALB and ITGA2 and therefore may have an anti- or a pro-tumor effect depending on specific environmental conditions and type of tumor [22].

Research is therefore moving towards molecules that can modulate Mfn2 expression. Melatonin, resveratrol, metformin, MitoQ and SS31 have been shown to increase Mfn2 expression and mitochondrial fusion restoring mitochondrial function; conversely, doxorubicin has been shown to decrease Mfn2 expression and stimulate fission [25]. Therefore, these molecules could represent new drugs to treat several diseases characterized by altered mitochondrial dynamics, including cancer.

In conclusion, Mfn2 is an example of the complexity of cancer biology, whereby the same molecule can exert a pro- or anti-tumor effect depending on type of tumor and microenvironmental conditions. Independently its paradoxical behavior, Mfn2 has shown to play a relevant role in cancer development and progression as well as to represent an extremely interesting potential therapeutic target.

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