International Journal of Cell Biology and luciferin/luciferase assays of muscle cells from ADOA patients showed a reduced ATP production mainly due to reduced complex I activity [129, 130]. On the other hand, in other studies, no energetic impairment was observed in lymphoblasts and muscle cells from ADOA patients [96, 97]. Whatever the case, consistent with the role of OPA1 in regulating mitochondrial dynamics, mitochondrial fragmentation is a common feature of ADOA with a severity score of the pathology directly proportional to the level of fragmentation observed [97, 98, 130]. Interestingly, ﬁbrob- lasts from ADOA patients also reveal a major sensitivity to death stimuli [98], in line with the antiapoptotic role of OPA1 described above [8]. 3.2.6. Other Neuropathies and Neurological Disorders. Among other neuropathies Leber hereditary optic neuropathy (LHON) has, as a primary cause, mutations in mtDNA [131]. Recently, a possible link with mitochondrial dynamics has been presented in a genome-wide linkage scan study, in which a mutation in Parl (the mitochondrial protease responsible for OPA1 cleavage, [132]) has been associated with LHON [133]. MFN2 is involved in the most common form of the auto- somal dominant axonal Charcot-Marie-Tooth (CMT2A) disease [99]. Moreover, ganglioside-induced diﬀerentiation- associated protein 1 (GDAP1), whose mutations cause an autosomal recessive form of CMT, appears to be related to mitochondrial ﬁssion in mammalian cells [100]. In addition, in a mouse model of apoptosis-inducing factor (AIF) deﬁciency, MFN1 levels are decreased in the cerebellum and are accompanied by death of Purkinije cells [134]. This phenomenon is generally observed in many neurological diseases such as autism, HD, AD, multiple system atrophy, and epilepsy [135]. Consistently, also in Mfn2 knock-out systems, death of Purkinije cells has been observed, conﬁrming a role for MFNs in protecting against lack of mtDNA and dysfunction of mitochondria in the cerebellum [136]. In the last decade, a link between neurological and lym- phatic aspects has emerged in schizophrenia [137]. Recently, a study in schizophrenia-derived lymphoblastoids revealed altered oxidative phosphorylation at level of complex I and clustering of mitochondria in a limited area of the cell, with a reduction in OPA1 expression levels [138]. To conclude, neurons rely on mitochondrial distribution, function, and dynamics to allow synapses and dendrites formation, energy supply, and quality control. The main properties of neurons constitute risk factors themselves if we consider the eﬀects of mitochondrial dysfunctions. First, they are cells highly demanded in energy; second, they have long processes connecting the soma to synapses and dendritic spines; third, they are long-lived postmitotic cells. Although knowledge is increasing about mitochondrial role in neurodegenerative diseases, much remains to be elucidated, in particular, why diﬀerent subpopulations of neurons are more vulnerable to mitochondrial fusion/ﬁssion imbalance and dysfunctions. 7 4. Neuroinﬂammatory and Autoimmune Diseases Little is known about the link between mitochondrial dynamics and neuroinﬂammatory or autoimmune diseases. In this section we present correlations described to date with multiple sclerosis (MS) and type I diabetes, as examples for this category of diseases (see Table 3). We then introduce some general outcomes about mitochondrial dynamics and T-cell compartment with the potential for opening up new perspectives regarding cellular mechanisms and clinical therapies for many pathologies. 4.1. Optic Neuritis and Multiple Sclerosis. Optic neuritis (ON) is a neuropathy characterized by demyelination of the optic nerve; it can be present by itself or as part of MS. Multiple sclerosis is an autoimmune disorder characterized by chronic demyelination of the central nervous system (CNS). The pathogenesis of MS is thought to involve self- antigen-reactive T lymphocytes that have the capacity to invade the CNS and to promote tissue damage. It is not rare to ﬁnd mtDNA mutations and mitochon- drial abnormalities in patients aﬀected by ON [143]. For instance, in a case of OPA1 mutation (S646L) ADOA has been shown to be associated with MS. This mutation leads to reduction of respiratory rates with lower ATP production [139], which is implicated in demyelination of axons in MS [140]. Interestingly, it has been shown that symptoms of autoimmune disorders, including MS, improve during pregnancy due, at least in part, to the expression of embryo- derived preimplantation factor (PIF). This protein is able to reduce neuroinﬂammation and to promote neural repair in the experimental autoimmune encephalomyelitis (EAE) model of MS, through a general decrease in proinﬂammatory cytokine and chemokine secretion, and a downregulation of proapoptotic factors and of activating and migrating proteins such as OPA1 [144]. 4.2. Type I Diabetes. Type I diabetes is an autoimmune disor- der caused by autoimmune elimination of insulin-producing β cells in the pancreas, clinically leading to increased glucose in blood and urine. Coronary endothelial cells from diabetic mice are characterized by fragmented mitochondria with a downregulation of OPA1 and an upregulation of DRP1 [141]. In addition, Prohibitin (Phb) has been shown to have a protective role in β cells [142]. Interestingly, phb-genetic ablation results in aberrant mitochondrial cristae structure and an increased apoptosis, dependent on increased prote- olytic processing of OPA1 [15]. Moreover, it has been shown that the embryo-derived preimplantation factor (PIF) also prevents type I diabetes in mouse models of this disease [145]. 4.3. Mitochondrial Morphology and T-Cell Function. The importance of mitochondrial localization and activity in T cell function is well established. T cells are activated at the so-called “immunological synapse” between a T cell and an antigen-presenting cell (APC) [146]. Mitochondria usually