Mitochondria: The Next (Neurode)Generation
2011; Cell Press; Volume: 70; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2011.06.003
ISSN1097-4199
AutoresEric A. Schon, Serge Przedborski,
Tópico(s)ATP Synthase and ATPases Research
ResumoAdult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders. Adult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders. Adult-onset neurodegenerative diseases are a large group of heterogeneous disorders characterized by the relatively selective death of neuronal subtypes. In most cases, they arise for unknown reasons, and are relentlessly progressive. Age is the most consistent and robust risk factor for neurodegenerative diseases, and thus, the number of patients is expected to increase dramatically in the years to come, especially in industrialized countries. For instance, the number of cases of Alzheimer's disease (AD) and other dementias, including Lewy body disease and frontotemporal dementia, was estimated by the World Health Organization in 2005 at almost 25 million individuals worldwide, with ∼5 million new cases annually, and is projected to more than double by 2025. Existing approved medicines provide only symptomatic relief, and their chronic use is often associated with deleterious side effects; none appear to modify the natural course of the diseases. Clearly, the development of effective therapies is hindered by our limited knowledge of the molecular mechanisms underlying these conditions. Despite the phenotypic diversity of neurodegenerative disorders, insights gained in the last decade into their pathophysiology, especially through genetics, have begun to reveal some underlying themes. These include disturbances in cellular quality control mechanisms (e.g., endoplasmic reticulum [ER] stress, defects in proteasomal and autophagic function, and accumulation and/or aggregation of misfolded proteins), oxidative stress, neuroinflammation, and impaired subcellular trafficking. Another pathogenic theme that has come to prominence, and which is the focus of this review, is the role of impaired mitochondrial function, not only as it pertains to defects in mitochondrial energy production, but also to mitochondrial dynamics (i.e., organellar shape, size, distribution, movement, and anchorage), communication with other organelles, and turnover. Of necessity, we have limited our discussion to a subset of neurodegenerative disorders (Table 1), focusing on those that best illustrate our central points. We recognize that this selection introduces a bias, yet the diseases we have chosen encompass the vast majority of patients afflicted with neurodegenerative disease, and thus should provide a faithful picture of the state of affairs regarding the role of mitochondria in neurodegeneration.Table 1Selected Neurodegenerative Disorders DiscussedNameFrequency per 100,000PresentationTypical Age of Onset (Yr.)Main Clinical ManifestationsMain Neuropathological FeaturesAlzheimer's disease (AD)1600>90% sporadic, 60 (often younger for familial cases)cognitive impairment primarily featuring memory problems (e.g. trouble in remembering recent events, the names of people and things); as the disease progresses, language (e.g. inability to recall vocabulary), perceptual skills, attention, constructive abilities, orientation, problem solving, and functional ability difficulties also arise, as well as behavioral and neuropsychiatric changes, including wandering, irritability, and labile affectsgross cerebral cortex atrophy (particularly in the temporal, parietal, and parts of the frontal lobes, and in the cingulate gyrus) due to a loss of neurons and synapses; these changes are associated with amyloid plaques and neurofibrillary tanglesAmyotrophic lateral sclerosis (ALS)1 to 3>90% sporadic, 30)progressive disorder of the peripheral nerves giving rise to weakness, muscle wasting, and sensory loss, predominantly in the feet and legs, but also in the hands and arms in advanced stages; often the first manifestation is difficulty in walkingdegenerative changes are seen in the peripheral nerves, where a reduction of large myelinated motor and sensory fibers is observed; spared fibers show damaged axons and myelin sheaths, with the distal part of the nerve often more affected than the proximal part; in some forms of CMT, the affected nerve may be enlarged and show “onion-bulb” formation of Schwann and fibroblast cellsHuntington's disease (HD)3 to 7familial;autosomal dominant;CAG trinucleotide expansions in the huntingtin gene40 to 50(of note, the greater the number of CAG repeats, the earlier the onset)often begins with personality changes (e.g. irritability) and mood disturbances (e.g. depression) followed by abnormal movements of a choreic nature, primarily of the face and fingers; as the disease progresses, chorea spreads, athetoid and dystonic monuments appear, and intellectual functions decline, giving rise to a dementiagross atrophy of caudate nucleus and putamen accompanied with mild frontal and temporal atrophy; the most salient neurodegenerative changes involve a loss of medium-size spiny neurons in the striatopallidal and striatonigral pathways associated with striatal gliosisHereditary spastic paraparesis (HSP)4 to 6familial;autosomal dominant, recessive, X-linked 90% sporadic,<10% familial∼60 (often younger for familial cases)tremor, slowness of movements, stiffness, poor balance; as the disease progresses, nonmotor manifestations arise, including dementia, constipation, sleep disturbances, and orthostatic hypotensionloss of pigmented neurons in ventral midbrain (e.g. substantia nigra pars compacta) and other pigmented nuclei (e.g. locus ceruleus, dorsal motor nucleus of the vagus); intraneuronal Lewy body inclusions; gliosisSpinocerebellar ataxias (SCA)1 to 4familial;autosomal dominant, recessive, X-linked;∼30 different gene mutations, but a CAG trinucleotide expansion (in different genes) is found in several forms 60progressive incoordination of gait, often associated with poor coordination of hands, speech, and eye movements; dementia, movement disorders such as parkinsonism, myoclonus, seizures, retinal degeneration, optic atrophy, and peripheral neuropathy are observed in some forms of SCAdegeneration of the spinal cord and the cerebellum, as well as many nuclei of the basal ganglia and the brainstem Open table in a new tab Many of the prominent adult-onset neurodegenerative disorders, such as AD, Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are primarily sporadic, i.e., they occur in the absence of any genetic linkage. However, in rare instances they can be inherited. The phenotypes of both the sporadic and familial forms of these diseases are essentially indistinguishable, implying that they might share common underlying mechanisms. We believe that this similarity justifies the analysis of rare genetic forms of a common sporadic disorder, as it could well illuminate the pathogenesis of both. Moreover, the familial counterparts of all of the common sporadic neurodegenerative disorders are due to mutations not just in a single gene, but in multiple distinct and often ostensibly dissimilar genes. This apparent genetic heterogeneity associated with specific syndromes should not come as a surprise, since thus far the taxonomy of neurodegenerative disorders rests on clinical, biochemical, and neuropathological criteria, lumping under the same label diseases that merely look alike. Nonetheless, this striking situation raises the possibility that however disparate these genes may appear to be, the functions of the respective gene products might intersect in common pathways. Furthermore, the observations that mutations in a specific gene can give rise to more than one distinct clinical phenotype (Chen et al., 2004Chen Y.Z. Bennett C.L. Huynh H.M. Blair I.P. Puls I. Irobi J. Dierick I. Abel A. Kennerson M.L. Rabin B.A. et al.DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).Am. J. Hum. Genet. 2004; 74: 1128-1135Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, Elden et al., 2010Elden A.C. Kim H.J. Hart M.P. Chen-Plotkin A.S. Johnson B.S. Fang X. Armakola M. Geser F. Greene R. Lu M.M. et al.Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.Nature. 2010; 466: 1069-1075Crossref PubMed Scopus (259) Google Scholar, Moreira et al., 2004Moreira M.C. Klur S. Watanabe M. Németh A.H. Le Ber I. Moniz J.C. Tranchant C. Aubourg P. Tazir M. Schöls L. et al.Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.Nat. Genet. 2004; 36: 225-227Crossref PubMed Scopus (218) Google Scholar, Pulst et al., 1996Pulst S.M. Nechiporuk A. Nechiporuk T. Gispert S. Chen X.N. Lopes-Cendes I. Pearlman S. Starkman S. Orozco-Diaz G. Lunkes A. et al.Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.Nat. Genet. 1996; 14: 269-276Crossref PubMed Google Scholar) suggest that while the disease classification scheme is useful clinically, it may be equally helpful to view different neurodegenerative disorders as reflecting different, and perhaps more nuanced, expressions of shared, fundamental underlying problems. In the last several years, 188 separate genetic loci have been associated with inherited forms of the eight adult-onset neurodegenerative syndromes that we have selected (AD, ALS, Charcot-Marie-Tooth disease [CMT], hereditary spastic paraparesis [HSP], Huntington's disease [HD], optic atrophy [OA], PD, and spinocerebellar ataxias [SCA] [Table 1]), and 106 genes have been identified (Table 2; see also Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/omim). In connection to the topic of this review, it is worth noting that of the 106 identified genes, at least 36 have some type of association to mitochondrial function, either directly (i.e., via proteins in known mitochondrial biochemical pathways and structure; 24 genes) or indirectly (i.e., via proteins that are not necessarily targeted to mitochondria, but that affect them secondarily, such as those associated with the communication between mitochondria and the ER; 12 genes) (Table 3). The fraction of mitochondrial-resident gene products associated with neurodegenerative disorders (24/106, or ∼23%) is well above the proportion expected by mere chance alone (∼8%, i.e., ∼1600 genes encoding mitochondrial proteins/∼20,000 total protein-coding genes), suggesting a predilection for defects in these organelles to be associated with late-onset neurodegenerative disorders. Based on the above discussion, let us start our journey through mitochondria and see where the path of human genetics leads us.Table 2Genes Associated with Inherited Forms of AD, ALS, CMT, HSP, HD, OA, PD, and SCATypeInh.GeneChromosomeAlzheimer disease (AD)AD1ADAPP21q21.3AD2?APOE19q13.32AD3ADPSEN114q24.2AD4ADPSEN21q42.13AD5??12p11–q13AD6??10q24AD7??10p13AD8??20pAD9??19p13.2AD10??7q36AD11??9p21.3AD12??8p12–q22AD13??1q21AD14??1q25AD15??3q22–q24AD16XL?Xq21.3Amyotrophic lateral sclerosis (ALS)ALS1ADSOD121q22.11ALS2 (J)ARALS22q33.1ALS3AD?18q21ALS4 (J)ADSETX9q34.13ALS5AR?15q15–q21ALS6ARFUS16p11.2ALS7AD?20p13ALS8ADVAPB20q13.32ALS9ADANG14q11.2ALS10ADTARDBP1p36.22ALS11ADFIG46q21ALS12AD/AROPTN10p13ALS13ADATXN212q24.12?ARSPG1115q21.1?ADVCP9p13.3Charcot-Marie-Tooth disease (CMT)CMT1AADPMP2217p12CMT1BADMPZ1q23.3CMT1CADLITAF16p13.13CMT1DADEGR210q21.3CMT1FADNEFL8p21.2CMT2A1ADKIF1B1p36.22CMT2A2ADMFN21p36.22CMT2BADRAB7A3q21.3CMT2B1ARLMNA1q22CMT2B2ARMED2519q13.33CMT2CADTRPV412q24.11CMT2DADGARS7p14.3CMT2EADNEFL8p21.2CMT2FAD/ARHSPB17q11.23CMT2GAD?12q12–q13.3CMT2HAR?8q21.3CMT2IADMPZ1q23.3CMT2JADMPZ1q23.3CMT2KADGDAP18q21.11CMT2LADHSPB812q24.23CMT2MADDNM219p13.2CMT2NADAARS16q22.1CMT4AARGDAP18q21.11CMT4B1ARMTMR211q21CMT4B2ARSBF211p15.4CMT4CARSH3TC25q32CMT4DARNDRG18q24.22CMT4EAD/AREGR210q21.3CMT4FARPRX19q13.2CMT4GAR?10q23.2CMT4HARFGD412p11.21CMT4JARFIG46q21CMTDIAAD?10q24.1–q25.1CMTDIBADDNM219p13.2CMTDICADYARS1p35.1CMTX1XLGJB1Xq13.1Huntington disease (HD)HDADHTT4p16.3Hereditary spastic paraplegia (HSP)SPG1XLL1CAMXq28SPG2XLPLP1Xq22SPG3AADATL114q22.1SPG4ADSPAST2p22.3SPG5AARCYP7B18q12.3SPG6ADNIPA115q11.2SPG7ARSPG716q24.3SPG8ADKIAA01968q24.13SPG9AD?10q23.3–q24.1SPG10ADKIF5A12q13.3SPG11ARSPG1115q21.1SPG12AD?19q13.11–q13.13SPG13ADHSPD12q33.1SPG14AR?3q27–q28SPG15ARZFYVE2614q24.1SPG16XL?Xq11.2SPG17ADBSCL211q12.3SPG18AR?8p12–p11.21SPG19AD?9q33–q34SPG20ARSPG2013q13.3SPG21ARSPG2115q22.31SPG22XLSLC16A2Xq13.2SPG23AR?1q24–q32SPG24AR?13q14.3SPG25AR?6q23.3–q24.1SPG26AR?12p11.1–q15SPG27AR?10q22.1–q24.1SPG28AR?14q21.3–q22.3SPG29AD?1p31.1–p21.1SPG30AR?2q37.3SPG31ADREEP12p11.2SPG32AR?14q12–q21SPG33ADZFYVE2710q24.2SPG34XL?Xq24–q25SPG35AR?16q21–q23.1SPG36AD?12q23–q24SPG37AD?8p21.1–q13.3SPG38AD?4p16–p15SPG39ARPNPLA619p13.2SPG40ADATL114q22.1SPG41AD?11p14.1–p11.2SPG42ADSLC33A13q25.31SPG44ARGJC21q42.13SPG45AR?10q24.3–q25.1?ARAIMP14q24Optic atrophy (OA)OPA1ADOPA13q29OPA2XL?Xp11.4–p11.21OPA3ADOPA319q13.32OPA4AD?18q12.2–q12.3OPA5AD?22q12.1–q13.1OPA6AR?8q21.13–q22.1OPA7ARTMEM126A11q14.1LHONMND genesmtDNAParkinson disease (PD)PARK1/4ADSNCA4q22.1PARK2ARPARK2/Parkin6q26PARK3AD?2p13PARK5ADUCHL14p13PARK6ARPINK11p36.12PARK7ARPARK7/DJ-11p36.23PARK8ADLRRK212q12PARK9ARATP13A21p36.13PARK10??1p32PARK11ADGIGYF22q37.1PARK12??Xq21–q25PARK13?HTRA22p13.1PARK14?PLA2G622q13.1PARK15ARFBXO722q12.3PARK16??1q32?ARSPG1115q21.1?ARNDUFV218p11.22Spinocerebellar ataxia (SCA)SCA1ADATXN16p22.3SCA2ADATXN212q24.12SCA3ADATXN314q32.12SCA4ADPLEKHG416q22.1SCA5ADSPTBN211q13.2SCA6ADCACNA1A19p13.2SCA7ADATXN73p14.1SCA8ADATXN813q21.33SCA8ADATXN8OS13q21.33SCA9AD??SCA10ADATXN1022q13.31SCA11ADTTBK215q15.2SCA12ADPPP2R2B5q32SCA13ADKCNC319q13.33SCA14ADPRKCG19q13.42SCA15ADITPR13p26.1SCA16ADCNTN43p26.2SCA17ADTBP6q27SCA18AD?7q22–q23SCA19AD?1p21–q21SCA20AD?11p13–q11SCA21AD?7p21.3–p15.1SCA22AD?1p21–q23SCA23AD?20p13–p12.3SCA24AR?1p36SCA25AD?2p21–p13SCA26AD?19p13.3SCA27ADFGF1413q33.1SCA28ARAFG3L218p11.21SCA29AD?3p26SCA30AD?4q34.3–q35.1SCA31ADBEAN-TK216q21SCAN1ARTDP114q32.1SCAR1ARSETX9q34.13SCAR2AR?9q34–qterSCAR3AR?6p23–p21SCAR4AR?1p36SCAR5AR?15q25.3SCAR6AR?20q11–q13SCAR7AR?11p15SCAR8ARSYNE16q25.2SCAR9ARADCK31q42.13SCAX1XL?Xp11.21–q21.3DRPLAADATN112p13.31FRDA1ARFXN9q21.11FRDA2AR?9p23–p11IOSCAARC10orf2/Twinkle10q24.31MIRASARPOLG15q26.1?ARANO103p22.1?ADSCN8A12q13.3Disease classification as listed in OMIM. Inh., Inheritance; AD, autosomal dominant; AR, autosomal recessive; M, mitochondrial; XL, X-linked. Open table in a new tab Table 3Genes Associated with Mitochondrial FunctionGeneSubtypeProteinFunction/CommentaIndicates whether the listed protein is known to be targeted directly to, or interacts indirectly with, mitochondria (Y, yes; N, no).Mito?Proteins associated with neurotransmission (12)ANO10Noneanoctamin 10; Ca2+-activated Cl- channelchloride transportNCACNA1ASCA6Ca2+ channel, α-1A subunitcalcium transportNEGR2CMT1D/4Eearly growth response 2 proteinregulates myelin transcriptionNGJB1CMTX1Gap junction protein β1 (connexin-32)role in myelinationNGJC2SPG44Gap junction protein γ2 (GJA12) (connexin-47)role in myelinationNITPR1SCA15IP3 receptor 1calcium transport (enriched in MAM)NKCNC3SCA13K+ channelpotassium transportNMPZCMT1B/2I/2Jmyelin protein P0myelin proteinNNDRG1CMT4DN-myc downstream regulated 1myelin maintenance protein, putativeNPMP22CMT1Aperipheral myelin protein 22myelin proteinNPRXCMT4Fperiaxinmyelin proteinNSCN8ANoneNa+ channel, type VIII, α subunitsodium transportNProteins associated with the cytoskeleton (25)ATL1SPG3A /40atlastin 1 GTPase (also called SPG3)ER-modeling dynamin; interacts with spastin and REEP1NATN1DRPLAatrophin-1may interact with spartin via AIP4NDNM2CMT2M/DIBdynamin-2microtubule-associated force-producing proteinNFGD4CMT4Hfrabin; FYVE/RhoGEF/PH domain containing 4binds, regulates actinNHSPB1CMT2Fheat shock protein 27 (HSP27)actin organization; binds microtubulesNHSPB8CMT2Lheat shock protein 22 (HSP22)chaperone; associated with autophagyNKIF1BCMT2A1kinesin 1B (CMT mutation in nonmito KIF1Bβ isoform)KIF1Bα isoform transports mitochondria, myelin mRNAsYKIF5ASPG10kinesin 5Amicrotubule motor protein; binds MiltonYL1CAMSPG1L1 cell adhesion moleculeaxonal glycoproteinNMTMR2CMT4B1myotubularin-related protein 2phosphoinositol-related phosphatase; interacts with SBF2NNEFLCMT1F/2Eneurofilament, light chain (NFL)intracellular transport to axons and dendritesYNIPA1SPG6nonimprinted in Prader-Willi/Angelman syndromesMg2+ transporter; interacts w ATL1NOPTNALS12optineurinfunction unclear; binds ubiquitin; also causes glaucomaYPLEKHG4SCA4puratrophin-1 (Purkinje cell atrophy associated)actin dynamics; has a spectrin repeat domainNREEP1SPG31receptor expression-enhancing protein 1binds spastin and atlastin; associates with microtubulesYSBF2CMT4B2myotubularin-related protein 13 (MTMR13)pseudophosphatase; interacts with MTMR2NSH3TC2CMT4CSH3 domain and tetratricopeptide repeats 2endosomal recycling with Rab11NSPASTSPG4spastinsevers microtubules; axonal branchingYSPG20SPG20spartinbinds microtubules; protein folding and turnover?YSPG21SPG21maspardin (ACP33 acidic cluster protein)axonal branchingNSPTBN2SCA5spectrin, β-IIIcytoskeletal proteinNSYNE1SCAR8synaptic nuclear envelope protein (nesprin-1)links organelles to the actin cytoskeleton; has spectrin repeatsNTTBK2SCA11Tau tubulin kinase 2phosphorylates tau and tubulinNVAPBALS8VAMP-associated protein Bassociates with microtubules; membrane transportNZFYVE27SPG33Zinc finger FYVE domain containing 27 (protrudin)interacts w spastin; may not be pathogenic (Martignoni et al., 2008Martignoni M. Riano E. Rugarli E.I. The role of ZFYVE27/protrudin in hereditary spastic paraplegia.Am. J. Hum. Genet. 2008; 83: 127-128Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar)NMitochondria-localized proteins (24)ADCK3SCAR9ubiquinone synthesis regulatory kinase (CABC1)CoQ synthesisYAFG3L2SCA28paraplegin-like AAA proteasemitochondrial protein degradationYATXN3SCA3ataxin-3 deubiquitinaseDNA repair; binds mitochondrial E3 ubiquitin ligase MARCH5YC10orf2IOSCATwinkle DNA/RNA helicase (PEO1)mtDNA replicationYFXNFRDA1frataxinmitochondrial iron metabolismYGDAP1CMT2K/4Aganglioside-induced differentiation-associated protein 1interacts with mitofusinsYHSPD1SPG13heat shock protein 60 (HSP60)mitochondrial chaperoneYHTRA2PARK13HtrA serine peptidase 2 (OMI)apoptosisYHTTHDhuntingtinmutant HTT is mitochondrial; interacts with microtubulesYMFN2CMT2A2mitofusin 2mitochondrial fusion; MAM integrityYmtDNALHONcomplex I subunits (mtDNA-encoded)respiratory chain functionYNDUFV2PDcomplex I subunit (nDNA-encoded)respiratory chain functionYOPA1OPA1dynamin-related GTPasemitochondrial fusionYOPA3OPA3dynamin-related GTPasemitochondrial fusion?YPARK7PARK7DJ-1atypical peroxidase; mitochondrial protein quality control?YPARKINPARK2ParkinmitophagyYPINK1PARK6PTEN-induced putative kinase 1mitophagyYPOLGMIRASmitochondrial DNA polymerase γmtDNA replicationYSNCAPARK1/4α-synucleinfunction unclearYSOD1ALS1superoxide dismutase, Cu,Zn-containingredox regulationYSPG7SPG7paraplegin AAA proteasemitochondrial protein quality controlYTDP1SCAN1tyrosyl-DNA phosphodiesterase 1topoisomerase I; DNA repairYTMEM126AOPA7transmembrane protein 126Afunction unknownYVCPALSvalosin-containing protein/p97retrotranslocation of proteins for proteasome (cyto → mito)YPotential relationship with mitochondria and/or mitochondria-associated ER membranes (MAM) (17)ALS2ALS2alsinguanine-nucleotide exchange factor for RAB5NAPPAD1amyloid precursor proteinpresenilin substrate (present in MAM)NATXN1SCA1ataxin-1RNA metabolismNATXN10SCA10ataxin-10binds GNB2 (mitochondrial), which binds MFN1 (mitochondrial)NBEAN-TK2SCA31BEAN-thymidine kinase 2 overlap regionTK2 is mitochondrial; BEAN is notNEGR2CMT1Dearly growth response 2 proteintranscription factorNGARSCMT2Dglycyl-tRNA synthetaseprotein synthesis (mitochondrial/cytosolic isoforms)YGIGYF2PARK11GRB10 interacting GYF protein 2enhances activation of ERK1/2, which is mitochondrialYKIAA0196SPG8strumpellin; AAA proteasebinds VCP; degrades MOM proteinsYLMNACMT2B1lamin A/Cnuclear membraneNLRRK2PARK8leucine-rich repeat Ser/Thr-protein kinase 2function not clearNPLA2G6PARK14phospholipase A2, group VI (iPLA2β)ER-mitochondrial crosstalk via ceramide (probably in MAM)YPPP2R2BSCA12PP2A regulatory subunit 2Bβsignaling (probably in MAM)YPSEN1AD3presenilin-1aspartyl protease; in MAMNPSEN2AD4presenilin-2aspartyl protease; in MAMNTARDBPALS10TAR DNA binding protein 43 (TDP43)DNA/RNA-binding protein, regulates transcription/splicingNTBPSCA17TATA box-binding proteintranscription factorNNo obvious relationship to mitochondria (26)AARSCMT2Nalanyl-tRNA synthetaseprotein synthesis (cytoplasmic)NANGALS9angiogenin; RNAse A (RNASE4)tRNA-specific RNAse; binds actin on endothelial cellsNATP13A2PARK9ATPase, P-typecation transporterNATXN2ALS13/SCA2ataxin-2function unknownNATXN7SCA7ataxin-7transcriptional regulationNATXN8SCA8ataxin-8affects RNA-binding protein MBNL1NATXN8OSSCA8ataxin-8 opposite strandfunction unknownNBSCL2SPG17seipinlipid droplet morphology; in ERNCYP7B1SPG5A25-hydroxycholesterol 7-α-hydroxylasecholesterol catabolism in ER, 1st stepNFBXO7PARK15F-box only protein 7ubiquitinationNFGF14SCA27fibroblast growth factor 14signalingNFIG4ALS11/CMT4Jpolyphosphoinositide phosphatase (SAC3)synthesis of phosphatidylinositol-3,5-bisphosphateNFUSALS6fused in sarcoma/translocated in liposarcoma (FUS/TLS)hnRNP proteinNLITAFCMT1Clipopolysaccharide-induced TNF-α factorstimulates monocytes/macrophagesNMED25CMT2B2mediator complex subunit 25transcriptional coactivatorNPNPLA6SPG39neuropathy target esterasedeacetylates intracellular phosphatidylcholine (in ER)NPRKCGSCA14protein kinase c, γ typesignaling; activated by Ca2+ and DAGNRAB7ACMT2BRas-related GTPase RAB7Aendosomal; vesicle transport; phagosome maturationNSETXALS4, SCAR1senataxinputative DNA/RNA helicaseNSLC16A2SPG22monocarboxylate transporter 8 (MCT8)thyroid hormone transporterNSLC33A1SPG42acetyl-CoA transporter (AT-1; ACATN1)ER-Golgi sialylationNSPG11SPG11, PDspatacsinfunction unknownNTRPV4CMT2Ctransient receptor potential cation channelosmoregulationNUCHL1PARK5ubiquitin C-terminal hydrolaseprotein degradationNYARSCMTDICtyrosyl-tRNA synthetaseprotein synthesis (cytoplasmic)NZFYVE26SPG15Zinc finger FYVE domain containing 26spastizin (FYVE-CENT); centrosomal proteinNa Indicates whether the listed protein is known to be targeted directly to, or interacts indirectly with, mitochondria (Y, yes; N, no). Open table in a new tab Disease classification as listed in OMIM. Inh., Inheritance; AD, autosomal dominant; AR, autosomal recessive; M, mitochondrial; XL, X-linked. Mitochondria are organelles present in all cells of the body (erythrocytes excluded), ranging from a few hundred to many thousands, depending on cell type. Maternally inherited, they are the locus for many of the body's “housekeeping” functions, including the biosynthesis of amino acids and steroids and the beta-oxidation of fatty acids; they also play a central role in apoptosis. However, the function that sets this organelle apart, and which is responsible for the cliché that mitochondria are the “powerhouses of the cell,” is the production of adenosine triphosphate (ATP), via the combined efforts of the tricarboxylic acid cycle and the respiratory chain/oxidative phosphorylation system (OxPhos). The respiratory chain is a set of biochemically linked multisubunit complexes (complexes I, II, III, and IV) and two electron carriers (ubiquinone/coenzyme Q and cytochrome c). It uses the energy stored in food to generate a proton gradient across the mitochondrial inner membrane, while at the same time transferring electrons to oxygen, producing water. The energy of the proton gradient drives ATP synthesis via ATP synthase (complex V); the ATP is then distributed throughout the cell. The central importance of mitochondria for cellular energy production is underscored by the discovery in the last 20 years of numerous syndromes resulting from OxPhos defects (DiMauro and Schon, 2003DiMauro S. Schon E.A. Mitochondrial respiratory-chain diseases.N. Engl. J. Med. 2003; 348: 2656-2668Crossref PubMed Scopus (794) Google Scholar). The mitochondrial respiratory chain is the product of a joint effort between the mitochondrial and nuclear genomes. Mitochondria harbor their own DNA (mtDNA) which is a 16.6 kb double-stranded circular DNA that encodes 13 of the ∼92 polypeptides of the OxPhos system (DiMauro and Schon, 2003DiMauro S. Schon E.A. Mitochondrial respiratory-chain diseases.N. Engl. J. Med. 2003; 348: 2656-2668Crossref PubMed Scopus (794) Google Scholar), while the nuclear DNA (nDNA) specifies ∼79 OxPhos structural polypeptides and more than 100 other proteins required for the proper incorporation of cofactors (e.g., iron-sulfur proteins, hemes, and copper) and for the assembly of the five respiratory chain complexes into an integrated system (Fernández-Vizarra et al., 2009Fernández-Vizarra E. Tiranti V. Zeviani M. Assembly of the oxidative phosphorylation system in humans: what we have learned by studying its defects.Biochim. Biophys. Acta. 2009; 1793: 200-211Crossref PubMed Scopus (86) Google Scholar). Patients with OxPhos dysfunction who carry mutations in either mtDNA or nDNA present with a host of clinical features, many of which are neurological, such as seizures, myoclonus, ataxia, progressive muscle weakness, stroke-like episodes, and cognitive impairment (DiMauro and Schon, 2003DiMauro S. Schon E.A. Mitochondrial respiratory-chain diseases.N. Engl. J. Med. 2003; 348: 2656-2668Crossref PubMed Scopus (794) Google Scholar). However, these manifestations do not typically overlap with either the clinical or the neuropathological hallmarks of any of our selected adult-onset neurodegenerative disorders (Table 1). Furthermore, to a remarkable degree, mutations in both mtDNA and nDNA that affect the integrity or functioning of the OxPhos complexes typically do not strike in adulthood, but rather in infancy (e.g., Leigh syndrome, which is a fatal, necrotizing encephalopathy). Yet, some patients with OxPhos dysfunction do succumb later, in their twenties or thirties (e.g., via Kearns-Sayre syndrome, which is a sporadically occurring, fatal, multisystem disorder featuring paralysis of the extraocular muscles, retinal degeneration, and heart block), but it is atypical for mitochondrial patients to survive much longer, and it is exceptional for any individual to experience an onset of an OxPhos disease beyond the age of 40. However, the age at onset and the severity of the disorder correlate well with the degree of ATP deficit caused by the mutation. Thus, “mild” mutations could theoretically give rise to a slowly progressive, late-onset neurodegenerative disease, such as AD or PD. Such mild mutations typically arise in one of two ways: either because the mutation per se does not cause a severe OxPhos impairment (e.g., mutations in complex I subunits cause Leber's hereditary optic neuropathy, or LHON [Sadun et al., 2011Sadun A.A. Morgia C.L. Carelli V. Leber's Hereditary Optic Neuropathy.Curr. Treat. Options Neurol. 2011; 13: 109-117Crossref PubMed Scopus (29) Google Scholar],
Referência(s)