International Journal of Cell Biology 5 Table 2: Mitochondrial dynamics and neurodegenerative diseases. Proteins involved Mitochondrial Mechanisms of pathophysiology (expression level and/or mutation) phenotype involving mitochondria Fragmentation, MFKNIDN1,REMSPI1FN,NFm2IS,u1Ota↑Pt↑Aio1n↓↓ itsdnKmnrtiuGrasidumtﬃrDouecbccntHpuhkedtroriicrnoenooi,gntdmfer,sreomdp,idfaeiliucmlefteorcxciptc,sithaPtosaioDnrienneHiddnria i[βbCmn7eDato7temw–tKro7aei1rl9ecocant]yio.codmtmnivaiptwictolcyeicut,xhhmaiolnDtunelRcdraeerPtrdii1eaobi,nanerntanaedlnhrcdaaKocnirtncitoeeedxnsin complex and COX. Pathology Alzheimer disease Huntington’s disease Parkinson disease Amiotrophic lateral sclerosis Autosomal dominant optic atrophy Charcot Marie Tooth Type 2 Thus, an alteration in Ca2+ homeostasis, due to abnor- mal ER-Mito crosstalk, results in impaired mitochondrial movement and consequently in neurodegeneration [101]. Moreover, Amyloid β, a constituent of extracellular neurite plaques in AD, is abundant in MAMs, contributing to interorganellar dysfunctions [102]. Altered MAM organi- zation has been proposed also for spinocerebellar ataxias (SCA), due to mutation in the regulatory subunit of Protein phosphatase 2A, PPPR2B [103], and for PD, due to mutation in the subunit 2b of phospholipase A2 (iPLAS2b). The latter is important in ER-mitochondria crosstalk during apoptosis mediated by ER stress [104]. 3.1.3. Mitochondrial Quality Control. The role of mitochon- drial quality control is becoming increasingly prominent in the explanation of neurodegenerative diseases such as Parkinson disease (PD) and others. A general mechanism of mitochondrial quality control relies on the PINK1/PARKIN MFN1, MFN2, OPA1 ↓↓ DRP1, FIS1 ↑↑ HTT mutation Parkin mutation or ↓↓ Pink1 mutation or ↓↓ DJ-1 mutation DRP1 ↓↓ MFN2 α-synuclein mutation LRRK2 mutation SOD mutation GEFmutation TDP-43 mutation OPA1 mutation MFN1 mutation GDAP1mutation Fragmentation; HTT interaction with DRP1, impaired mitochondrial increased calcineurin and DRP1 traﬃcking, defects in activity, redistribution of kinesin and SDH (complex II) and dynein motor complexes in striatal Aconitase. neurons [80–82]. Altered interaction between Fragmentation, mitochondria and motor complexes, impaired mitochondrial impaired mitophagy of damaged traﬃcking. mitochondria in substantia nigra [74, 75, 83–86]. Fragmentation, disruption of cristae Toxicity associated to the formation structure with expansion of aggregates of mutant SOD, in of IMS, impaired subsarcolemmal region of muscles mitochondrial and anterior horn neurons of lumbar traﬃcking, complex I spinal cord [87–93]. dysfunctions. IFrdaygsmfuenncttaiotinosn., complex r[Me9t4aij–no9ar8ls]ge.annsgitliivointycteollsdaenatdhosptitmicunlierinve (FmGruaDgt)AmoPer1netmlaotuniotg)na.t(iMonFN1 aECMlRatFel-crNmeiu1dimt:olpocsrcooiagnblnidazarbalitllaiyinotaegnltt[hoe9erf9arG]itn;iDoGgnADaPinnA1dP[11:00]. pathway, deeply studied in vitro. Brieﬂy, loss of Δψ induces stabilization of PINK1 on the OMM and allows PARKIN recruitment on mitochondria. This, in turn, leads to ubiq- uitination of mitochondrial substrates and their interaction with p62 and LC3 so as to induce the engulfment of mitochondria inside the autophagosome [24, 25]. MFNs, for example, are ubiquitinated in a PARKIN-dependent manner [105] and then degraded by proteasome [106]. Others showed that DRP1 stability is also regulated by PARKIN [107]. 3.2. Focus on the Pathologies. Coming back to the patholo- gies, in this paragraph, we will focus on the links between some of them and the mitochondrial dynamics. 3.2.1. Alzheimer Disease. The main clinical feature of Alzheimer disease (AD) is the accumulation of extracellular