International Journal of Cell Biology 3 Table 1: Mitochondrial dynamics and cancer. Pathology Diﬀerent types of tumors Proteins involved (expression level) MFN1, MFN2, OPA1 ↓↓ DRP1, FIS1 ↑↑ Mitochondrial phenotype Fragmentation. damage, for example, induces ﬁssion, which, in turn, allows mitochondria to be engulfed by the autophagosomes and then degraded [23]. Autophagy represents a cellular self-degradation process involved in the degradation of bulk cytoplasmic components, proteins, or entire organelles in basal or nutrient depleted conditions. This process is also described as macroautophagy and is diﬀerent from the selective autophagy. The latter is responsible for selective degradation of damaged and dysfunctional organelles, and, thus, it represents the quality control system for mitochondria [23]. In case of dam- age, mitochondria undergo fragmentation, and PARKIN is recruited to the organelles in a PINK1-dependent manner, allowing their engulfment into the autophagosome and their selective degradation (mitophagy) [24, 25]. On the other hand, when macroautophagy is induced, mitochondria elon- gate, being so spared by autophagosomes to ensure the major energy supply required by the cell in starving condition [26]. Besides their role in mitochondrial quality control, PINK1 and PARKIN have also a role in regulating mitochondrial dynamics. Moreover, BNIP3, a BH3-only member of the Bcl-2 family, enlarges the number of proteins crosstalking between autophagy and mitochondrial dynamics [27]. Its misregulation has implications in the development of mus- cular atrophy [28]. The existence of a crosstalk between autophagy and the mitochondrial dynamics machinery, as well as with the apoptotic process, opens new questions and is in need of further investigations. To reinforce the idea of an intimate connection between mitochondrial dynamics and function, recently published data have revealed that in vivo genetic ablation of fusion (Opa1 knock-out mice [29, 30], Mfn1/Mfn2 double knock- out mice [5]), or ﬁssion (Drp1 knock-out mice [31]) proteins results in early embryonic lethality. Other data reveal mutations or abnormal regulation of mitochondria shaping proteins in many pathological conditions, as we will see below. 2. Cancer According to the classiﬁcation of the hallmarks of cancer by Hanahan and Weinberg [32], a cell needs a multistep process to become tumoral and, later on, to develop metastasis. Mitochondria are crucially positioned for establishing resis- tance to cell death and sustaining proliferative signallings. Their role is essential for the metabolic shift to glycolysis (the so-called Warburg eﬀect), common in tumoral cells. Increasing evidence shows the involvement of mitochondrial dynamics in cancer development (see Table 1). Mechanisms of pathophysiology involving mitochondria Inhibition of TCA cycle and oxidative phosphorylation, mitochondrial membrane permeabilization; ﬁssion accompanied by ROS production, polarization and chemotaxis of lymphocytes and tumoral cells [42–45]. 2.1. Escaping Cell Death and Regulating Mitochondrial Mor- phology: A Role for the Bcl-2 Family Proteins. Escaping death signals is one of the ﬁrst characteristics of a tumoral cell. Bcl- 2 family proteins play an important role in balancing life and death signals [33] converging on mitochondria and, at the same time, in regulating changes in mitochondrial morphol- ogy. Generally, prosurvival signals are associated with elon- gated mitochondria, while cell death is usually accompanied by mitochondrial fragmentation. BCL-2 is a tumoral marker overexpressed in many lymphomas contributing to resistance to cell death [34–36]. CED-9, the homolog of BCL-2 in C. ele- gans, is able to interact with MFN2-inducing mitochondrial fusion [37]. BCL-XL promotes instead ﬁssion stimulating the DRP1 GTPase activity [38]. The proapoptotic BAK and BAX stabilize DRP1 on mitochondria promoting ﬁssion [39], indeed, Bak −/−Bax −/− cells have an elongated mitochon- drial network [40]. Interestingly, BAX colocalizes with DRP1 and MFN2 at sites of ﬁssion so promoting mitochondrial membrane permeabilization [39]. Finally, consistent with their proapoptotic role, NOXA and PUMA trigger DRP1- dependent mitochondrial fragmentation [41]. 2.2. Metabolic State and Mitochondrial Shape Changes. Another feature of tumoral cells is the already mentioned shift from the production of ATP by oxidative phosphoryla- tion to a glycolytic phenotype despite the presence of oxygen [32]. It is not yet clear if this metabolic modiﬁcation is an adaptation to a hypoxic microenvironment or the result of defects in OXPHOS respiration. Nevertheless, the existence of a double relationship between mitochondrial morphology and metabolic state is, however, increasingly evident. In OXPHOS cells, mitochondria appear elongated (State III); in glycolytic cells, they have a more fragmented phenotype (state IV) [46, 47]. The molecular mechanism underlying this phenomenon involves fusion proteins: reduced levels of MFN2, MFN1, or OPA1 results in the inhibition of TCA cycle, the decrease of oxidative phosphorylation, and the increase of glycolysis and lactic fermentation [42, 43]. Moreover, in a tumoral mass, the cellular response to hypoxia triggers mitochondrial elongation, dependent on HIF1; this, in turn, increases the resistance to apoptotic stimuli [48]. On the other hand, an eﬃcient oxidative phosphorylation, and the consequent optimal mitochondrial membrane potential, (Δψ), is necessary for mitochondrial fusion [49, 50]. 2.3. Cell-Cycle Regulation: When Cell Division Means Mito- chondrial Fragmentation. It has been shown that mitochon- dria undergo fragmentation during the S and M phase of