6 deposits of amyloid β (Aβ) plaques and tau-containing intra- cellular neuroﬁbrillary tangles in the brain, these leading to progressive neuronal death. From a morphological point of view, neurons expressing amyloid protein precursor (APP), or Amyloid β, show abnormal levels of mitochondrial shap- ing proteins with downregulation of MFNs and OPA1 and upregulation of DRP1 and FIS1 [69, 70, 108, 109]. Amyloid β interacts with DRP1 [77], promoting mitochondrial ﬁssion in a DRP1 S-nitrosilation-dependent manner [110, 111]. Tissues from patients aﬀected by AD show mitochondria with disrupted cristae structure [112] and reduction of the number of mitochondria in dendrites [69]. Interestingly, although cell-cycle-coupled events are rare in postmitotic cells, the activity of CDK1 and CDK5 is enhanced in AD. CDK5 phosphorylates tau [78], while a high level of phosphorylated DRP1 at Serine 616 appears to be dependent on both CDK1 and protein kinase C δ (PKC δ) [79], as it has been shown in rat primary neurons. 3.2.2. Huntington’s Disease. A mitochondrial connection is emerging also in Huntington’s disease (HD); mitochon- drial succinate dehydrogenase (SDH, complex II), aconitase defects [80], and mtDNA damage [113] have been reported in in vivo models of HD. In addition, 3-nitropropionic acid, an irreversible inhibitor of complex II, has been shown to induce mitochondrial fragmentation and HD-like symptoms in rats and mice [81]. Of note is that primary striatal neurons from HD mouse models reveal mitochondrial fragmentation [114] with an alteration of mitochondrial shaping proteins in the brain (DRP1 and FIS1 upregulation, OPA1 and MFN1 downregulation) [115]. Mutant HUNTINGTIN is able to bind DRP1, increasing its GTPase activity and inducing mitochondria fragmentation both in mice and in human brains [82]. This phenotype is rescued by MFNs or DRP1- K38A-dominant negative overexpression and by the use of two DRP1 inhibitors, mdivi1 or miR-499 [116–120]. 3.2.3. Parkinson Disease. Independent studies identiﬁed α- synuclein, Pink1, Parkin, DJ-1, and Leucine-rich repeat kinase 2 (LRRK2) as commonly mutated genes in Parkinsonism. α- SYNUCLEIN and LRRK2 have been proposed as playing a role in microtubule organization and, thus, in mitochondrial traﬃcking [74, 75]. PINK1 and PARKIN are key proteins in mitochondrial quality control [24, 25], as we discussed above. Interestingly, opposite to what has been observed in drosophila [121, 122], downregulation of PINK1 or PARKIN by siRNA in neuroblastoma cells leads to mitochondrial fragmentation [83]. Also in this case, this fragmentation is rescued by genetically forcing the mitochondria mor- phology equilibrium towards fusion, or by treatment with the calcineurin inhibitor FK506 [84, 85]. The recruitment of PARKIN to mitochondria has been nicely investigated in diﬀerent models; generally, it has been shown that upon mitochondrial membrane depolarization PARKIN is recruited to mitochondria both in primary and cultured cell models [25], but this mechanism is also inhibited in primary neurons [86]. The apparent discrepancy in the results among diﬀerent experimental models could be explained, at least in International Journal of Cell Biology part, by the observation that those cell models rely on diﬀer- ent bioenergetic systems. It has been shown, in fact, that, in primary rat neurons, which largely depend on mitochondrial respiration to produce ATP, or in nonneuronal cells forced to mitochondrial respiration, PARKIN fails to translocate to mitochondria after membrane depolarization in contrast to what is observed in cells relying on glycolytic production of ATP [86]. This suggests that additional regulatory and/or protective mechanisms against mitochondrial damage have to be investigated in neurons. We should also consider that, in all these studies, loss of Δψ is obtained by treating cells with high concentrations (or for long terms) of the protonophores CCCP or FCCP. A common challenge in the next future will be the identiﬁcation and the use of more physiological stimuli to induce mitochondrial damage, and mitophagy, to better mimic the in vivo mechanism of patho- physiology of neurodegenerative diseases. By this way, it will be possible to clarify some of the discrepancies remaining in the ﬁeld such as, for example, the diﬀerences observed so far for the PINK1/PARKIN functional interaction in various cell lines; or considering the loss of Δψ (artiﬁcially induced and forced in all the in vitro experiments performed until now) as the only event triggering mitophagy, another point highly debated and controversial to date. A mouse model of DJ-1 knockout presents mitochon- drial fragmentation [123], increased ROS production, and reduced respiration rates accompanied by basal autophagy impairment [124]. Complex I dysfunctions are common in PD, and its inhibition, by rotenone or 6-hydroxydopamine (6-OHDA) treatment, results in a DRP1-dependent mito- chondrial fragmentation in neurons [125, 126], so suggesting another link between bioenergetic dysfunctions and altered mitochondrial dynamics in neurodegenerative diseases. 3.2.4. Amyotrophic Lateral Sclerosis. In the 20% of patients aﬀected by an autosomal dominant form of amyotrophic lateral sclerosis (ALS), a gain of function mutation in SOD1 has been detected [87]. Defects of complex IV activity and mtDNA rearrangement have been also reported in patients aﬀected by ALS [127, 128]. Abnormal aggregation of mitochondria is common in the subsarcolemmal region of muscles and in the anterior horn neurons of the lumbar spinal cord [88, 89]. At ultrastructural levels, in the case of ALS, mitochondria show disorganized cristae with expansion of intermembrane space (IMS) [90, 91]. Of note, the overexpression of a mutated form of SOD1 in ALS (SOD1- G93A) induces fragmentation of mitochondria in NSC-34 motoneuronal-like cells [92]. Moreover, motor neurons from mice overexpressing SOD1-G93A show impaired mitochon- drial fusion both in axons and in the cell body with impaired retrograde axonal transport and reduction of frequency and speed of the movement [93]. 3.2.5. Autosomal Dominant Optic Atrophy. Opa1 mutations are responsible for the autosomal dominant optic atrophy (ADOA) [94, 95]. Contrary eﬀects regarding oxidative phos- phorylation impairment related to this disease have been published. Phosphorus magnetic resonance spectroscopy