4 the cell cycle to allow a limitation of the mutation rate during DNA replication, through a temporary decrease of oxidative phosphorylation (which is the main source of ROS). Such fragmentation is also necessary for an equal segregation of mitochondria between the daughter cells [51, 52]. This process is mainly regulated by CDK1/Cyclin B complex, which phosphorylates DRP1 at the beginning of the S phase, resulting in DRP1 recruitment on mitochondria and subsequent mitochondrial fragmentation [53]. Thus, in normal conditions, the fragmentation of mitochondria, required during cell division, is a DRP1- and CDK1- dependent process, but in many tumors the cell cycle is dysregulated, and CDK1 activity becomes altered. It remains to be investigated whether this has an eﬀect also on the morphology of mitochondria. 2.4. ROS Production and Mitochondrial Fragmentation. To continue this overview, ROS can be considered as both initiator factors of the tumor (inducing genome and mtDNA mutations) and enhancing factors giving a higher rate of proliferation to the cells [54, 55]. ROS production is mainly attributed to mitochondria, at the level of respiratory chain, and, in case of mitochondrial fragmentation, it is enhanced. Signiﬁcantly, ionizing radiation is accompanied by ROS production and mitochondrial fragmentation in a DRP1- dependent way, so contributing to genome instability and carcinogenesis [44]. Interestingly, clinical studies of lung adenocarcinoma reveal a role for DRP1, independent of the mitochondrial morphology. In this tumor, DRP1 is overexpressed, but is sequestered in the nucleus by hHR23A, so avoiding its localization on mitochondria and conferring resistance to cisplatin [56]. A central role for mitochondrial dynamics also emerges in other studies. IL-6 dependent cancer cachexia is characterized by MFNs mRNA reduction and FIS1 mRNA upregulation [57]. FIS1 is also upregulated in some subtypes of human malignant melanoma [58]. In a more general way, cancer cells share characteristics with stem cells, in particular regarding mitochondrial mor- phology, localization, function, and mtDNA content [59]. Of note, in embryonic stem cells, there is a growth factor erv-1- like (GERF)-dependent DRP1 downregulation, which leads to mitochondrial elongation and an enhanced cell viability [60]. Finally, in lymphocytes mitochondria ﬁssion and relocal- ization to the uropod are necessary for the polarization and chemotaxis of these cells [45], so unravelling a possible role for mitochondrial morphology also in metastasis formation, where the acquisition of migratory capability represents the main feature of a metastatic cell phenotype. 3. Neurodegenerative Diseases 3.1. Beyond the Morphology: Physiological Mechanisms Af- fected by Altered Mitochondrial Dynamics in Neurons. Before starting the examination of diﬀerent pathologies directly related to mitochondrial dynamics failure or imbalance (see Table 2), we would like to give an overview of some of International Journal of Cell Biology the possible mechanisms whereby mitochondrial dynamics alterations can lead to neurodegeneration: aberrant mito- chondrial traﬃcking, altered interorganellar communication and impaired mitochondrial quality control [61]. 3.1.1. Mitochondrial Traﬃcking. Neurons, especially motor neurons, are characterized by long axons up to more than one meter at the end of which synapses exert their role in cellular-cellular communication. The resulting importance of mitochondrial anterograde transports to the synapses (to ensure ATP production necessary for neurotransmitters vesicles to be discarded [62]) and of retrograde movement to the soma of the cell are both clearly evident. Mitochon- dria rely on dynein/dynactin motor for the anterograde movement, on kinesin motor for the retrograde one, and on MIRO and MILTON as an additional mitochondrial linker and regulatory proteins [63]. Thus, a defect in the cellular motors, or in the mitochondria compartment to be loaded as cargo, could result in a mitochondrial deﬁcit at synapses and in neurodegeneration. There is no direct correlation described so far in patients although, in some sporadic cases of Alzheimer disease (AD), traﬃcking alteration has been observed due to mutation in Kinesin1 [64]. That said, increasing data are emerging in experimental models. Anterograde and retrograde traﬃcking is altered in Amyotrophic lateral sclerosis (ALS) mouse models in which SOD1 [65, 66], guanin-nucleotide exchange factor (GEF) and TAR DNA-binding protein 43 (TDP-43) are mutated [67, 68]. Noteworthy, a role for mitochondrial traﬃcking impairment has been demonstrated in pathologies not only aﬀecting long axon neurons but also short cortex and hippocampal ones (this is the case of Alzheimer disease— AD—models) [64, 69, 70]. Similar observations come from works in a Huntington’s disease (HD) mouse model, in which mutated Htt (the gene of HUNTINGTIN protein) is able to block mitochondrial movement [71] and causes a redistribution of kinesin and dynein in primary cortical neurons [72]; in Parkinson disease (PD) cellular and mouse models where PINK1 has been shown to interact with MIRO and MILTON [73], as well as with α-SYNUCLEIN, LRRK2, and PARKIN, to disrupt the microtubule network in the cell [74–76]. 3.1.2. Mitochondria-Associated Membranes and Ca2+ Homeo- stasis. In recent decades, a functional role for mitochon- dria-ER interactions and Ca2+-signalling implications has emerged [6]. The sites where these two organelles interact are deﬁned as mitochondria-associated membranes (or MAMs), and MFN2 activity is pivotal in ER-mitochondria tethering and MAM formation. MAMs have a role in regulating calcium crosstalk between ER and mitochondria, so avoiding Ca2+ overload in mitochondria in physiological condition and revealing, thus, an unexpected connection with mito- chondrial traﬃcking. In fact, MIRO is a calcium-binding protein; it has been proposed that only in calcium unbound state (low local Ca2+ concentration) is it able to interact with MILTON, so allowing movement of mitochondria [101].