Mitochondria are key organelles in the cell, hosting essential functions, from biosynthetic and metabolic pathways, to oxidative phosphorylation and ATP production, from calcium buffering to red-ox homeostasis and apoptotic signalling pathways. Mitochondria are also dynamic organelles, continuously fusing and dividing, and their localization, size and trafficking are finely regulated. Moreover, in recent decades, alterations in mitochondrial function and dynamics have been implicated in an increasing number of diseases. In this review, we focus on the relationship clarified hitherto between mitochondrial dynamics and cancer, neurodegenerative and neuroinflammatory diseases. 1. Introduction In eukaryotic cells, the role of mitochondria is pivotal both in providing essential molecules and signals for life and in amplifying signals of death. In regard to the cell life, mitochondria produce most of the ATP necessary to the cell through oxidative phosphorylation, and they are involved, among the others, in TCA cycle, fatty acid metabolism, hemesynthesis, and gluconeogenesis. As regards the cell death, mitochondria are involved in and red-ox homeostasis, which are dysregulated during cell death, and they release proapoptotic proteins, such as cytochrome c, SMAC/DIABLO, AIF, Endo G, and Omi/HTRA2, after mitochondrial membrane permeabilization and cristae remodeling [1–3]. Moreover, mitochondria are highly dynamic organelles that can fuse and divide, forming an interconnected network or fragmented units inside the cell, according to different stimuli impinging on the fusion/fission machinery, represented by the mitochondria shaping proteins: MFN1, MFN2, OPA1, regulators of fusion, and DRP1, FIS1, MFF, and MIEF1, which modulate fission [4] (see Figure 1(a)). Figure 1: The dynamic nature of mitochondrial shape. (a) Main proteins involved in mitochondrial shape changes are depicted. In fused unopposed condition, DRP1 is phosphorylated and sequestered in the cytoplasm. Once dephosphorylated, it is recruited to the OMM where it oligomerizes and interacts with FIS1, MFF, or MIEF inducing constriction of membranes and, eventually, fission of mitochondria. MFNs homo- and heterooligomerization on the OMM and oligomerization between long and short isoform of Opa1 on the IMM control fusion of mitochondrial membranes. Additional proteins affecting mitochondrial shape are also shown. (b) Mitochondrial morphology in Jurkat cells overexpressing yellow fluorescent protein targeted to mitochondria. The upper panel shows a network of elongated and interconnected mitochondria. In
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