Critical ReviewMitochondrial Involvement inNeurodegenerative Diseases

G!abor ZsurkaWolfram S. Kunz*

Department of Epileptology and Life and Brain Center, University Bonn,Bonn, Germany

AbstractThe classical bioenergetical view of the involvement ofmitochondria in neurogeneration is based on the fact thatmitochondria are the central players of ATP synthesis inneurons and their failure leads to neuronal dysfunction andeventually to cell death. Mutations in at least 39 genes ininherited neurodegenerative disorders seem to alter directlyor indirectly mitochondrial function. Most of these mutationsdo not directly affect oxidative phosphorylation, but actthrough disturbed mitochondrial dynamics and qualitycontrol. This, however, does not invalidate the bioenergetic

hypothesis. Neurodegeneration is not necessarilyassociated with a gross failure of ATP production, but mightrather be a consequence of local insufficiencies of ATP sup-ply in critical compartments of neurons, like the presynapticterminal. We hypothesize that slow disease progression, atleast in a subgroup of neurodegenerative diseases, can beexplained by the parallel action of subcellular ATP insuffi-ciency and clonal expansion of somatic mitochondrial DNAmutations, and particularly deletions. VC 2013 IUBMB Life,00:000–000.

Keywords: mitochondria; neurodegenerative diseases; reactive oxygenspecies

Introduction: Specific Properties ofNeuronal MitochondriaIt is a well-known fact that mitochondrial oxidative phospho-rylation provides the major source of ATP in neurons. Fromthe classical viewpoint, adequate levels of ATP are essential tomaintain the neuronal plasma membrane potential via thesodium–potassium ATPase, which consumes about 40% of theenergy (1). In addition, mitochondria are an important intra-cellular Ca2! sequestration system (2,3), and especially synap-tic mitochondria are indispensible for neurotransmitterreserve pool mobilization in the presynaptic compartment (4).Due to these important features, mitochondria can modulateneuronal excitability and synaptic transmission (5,6). In addi-

tion, more recent evidence shows that mitochondria in neu-rons are highly dynamic organelles undergoing extensivefusion, fission, and have sophisticated mechanisms for qualitycontrol, which is extremely relevant for a dependable long-lasting function of these postmitotic cells, working in highlyspecialized networks and being not subject to further selectionmechanisms. This review summarizes recent evidence show-ing the link of dysfunctional mitochondria and progressiveneurodegeneration in certain neurodegenerative disorders.

Mitochondrial Dynamics in NeuronsIn the neuronal soma, mitochondria undergo extensive fusionand fission events enabling adequate content mixing. Themitofusins, Mfn1 and Mfn2, are located in the outer membraneand are involved in the early events of membrane fusion (7,8),whereas the dynamin-related protein Opa1 is inner membraneassociated and essential for inner membrane fusion (9). Muta-tions in the MFN2 and OPA1 genes are associated with neuro-degenerative diseases—Charcot-Marie-Tooth neuropathy type2A (CMT2A) and dominant optic atrophy (OA), respectively(10–12). Neurodegeneration appears to be the prominent phe-notype in mice with a targeted mutation in MFN2, and cellslacking mitochondrial fusion show a severe defect in theirrespiratory capacity (13,14). Particularly, fusion events allowefficient complementation of damaged proteins, DNA and RNA.

*Address for correspondence to: Wolfram S. Kunz, Division ofNeurochemistry, Department of Epileptology, University Bonn MedicalCenter, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. Tel.:!49-228-6885290. Fax: !49-228-6885236. E-mail: wolfram.kunz@ukb.uni-bonn.de.Received 9 November 2012; Revised 6 December 2012; accepted 6December 2012DOI: 10.1002/iub.1126Published online in Wiley Online Library(wileyonlinelibrary.com)

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On the other hand, vesicular mitochondria which are formedas result of fission events from the mitochondrial network arethe cargo of axonal transport of mitochondria into the presyn-aptic compartment (Fig. 1). Here, high ATP requirementsresult from ion pumps, pumps required for sequestration ofneurotransmitters, and ATP-dependent reserve pool vesiclemobilization (4). The anterograde axonal transport of mito-chondria along microtubules (Fig. 1) is performed by theaction of two cargo adaptor proteins—Miro and Milton, whichlink mitochondria to kinesin-1 motors in neurons. Miroattaches the mitochondrial outer membrane with the mito-chondria-specific adaptor protein Milton, which is directlylinked to the kinesin-1 heavy chain (15–17). Additionally to itsadaptor function, Miro is a calcium-binding protein (18) andworks as sensor for local Ca2!—and ATP—concentrations. Inthe Ca2!—free state, Miro binds Milton and mitochondria areattached to microtubules and can be transported. At higherCa2!—concentrations, Miro is unable to bind Milton, andtherefore, the cargo mitochondria are detached from themicrotubules (19). The specific Ca2!-sensor properties ofMiro enable effective mitochondrial transport along microtu-bules only when the local Ca2!-concentration is low and theATP concentration is high (20,21). Mitochondria are clearedfrom the presynaptic compartment by retrograde transportwith the use of dynein motor proteins linked via the adaptorprotein dynactin (22). This mechanism ensures sufficient andeffective distribution of the ATP producers directly to the

sites of high energy consumption to avoid large gradients ofadenine nucleotide concentrations. To have sufficient amountsof well functioning, localized ATP producers is essential forlarge cells and in particular for neurons. That might be one ofthe major reasons why impairment of mitochondrial dynamicsand, consequently, also of axonal transport is one of the mostfrequent causes for neurodegenerative disorders (see section‘‘Neurodegenerative Diseases with Evidence for Direct Mito-chondrial Involvement,’’ below).

Mitochondrial Quality ControlA relevant aspect of the long-term maintenance of mitochon-drial function in postmitotic cells such as neurons is an effec-tive quality control. This issue gained a rapidly increasing in-terest in the last years. In opposite to fast dividing cells,neurons (integrated in complex networks) cannot be simplyeliminated by selection processes if they have compromisedmitochondria. Neuronal mitochondria, therefore, need mecha-nisms to eliminate damaged proteins which occurs, for exam-ple, by the AAA (ATPase associated with diverse cellular activ-ities) protease paraplegin (SPG7), which is mutated inhereditary spastic paraplegia (HSP) 7, but also by the paraple-gin-related protease AFG3L2, which is mutated in SCA28 (23).Other routes for mitochondrial protein degradation exist also,because outer membrane proteins can be back transportedinto the cytosol for subsequent clearance by the proteasomewith the mitochondrially targeted valosin-containing protein(VCP/p97, also a AAA protease (24)), which is mutated in aspecific form of inherited amyotrophic lateral sclerosis (ALS).

In addition to the quality control on the protein level,recent evidence suggests also the operation of a quality controlon organelle level. The prerequisite of a functional organelle-level quality control is that neurons must be able to distinguishbetween ‘‘intact’’ and ‘‘damaged’’ organelles. This distinctionis apparently based on the potential of the mitochondrial innermembrane (Dw) and the rate of generation of reactive oxygenspecies (ROS). Mitochondria are recognized as ‘‘damaged,’’ iftheir mitochondrial membrane potential is low due to a dys-functional respiratory chain and, correspondingly, their gener-ation rate of ROS is high due to the inhibition of electron trans-fer (see below, section ‘‘Mitochondrial Formation of ROS andNeurodegeneration’’). These damaged mitochondria are elimi-nated via selective mitophagy (25) with the involvement ofPINK1 and parkin, being mutated in the PARK6 and PARK2forms of inherited parkinsonism (see section ‘‘Neurodegenera-tive Diseases with Evidence for Direct Mitochondrial Involve-ment’’). However, it is difficult to imagine that disassembly ofwhole mitochondria is an energetically favorable way of qual-ity control. Rather, different pathways to restore the functionof damaged mitochondria probably represent a more economi-cal solution. Such pathways include i) the above mentionedquality control on protein level and ii) homogenization oforganellar contents by fusion and fission within the dynamicmitochondrial network (cf. Fig. 1). The mixing of the matrixcontent of a few damaged mitochondria with the larger matrix

Scheme illustrating axonal transport and mitochondrialdynamics in neurons. The high energy demand in thepresynaptic compartment is illustrated by the orangeshading. Intact mitochondria are shown in green,whereas red indicates damaged mitochondria. Miroand Milton are implicated in the specific linkage of mito-chondria to the kinesin-1 motor, relevant for antero-grade transport (blue symbols). Damaged mitochondriaare cleared from the presynaptic compartment in retro-grade transport by dynactin linking to a dynein motor(purple symbols). The damaged organelles are eitherremoved by mitophagy or regenerated by content mix-ing through fusion with intact mitochondria. [Color fig-ure can be viewed in the online issue, which is availableat wileyonlinelibrary.com.]

FIG 1

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pool of the intact mitochondrial network potentially allows anefficient complementation of biomolecules (26). Therefore,effective mitochondrial ‘‘content mixing’’ is able to reduce thedeleterious effects of damaged proteins and RNAs and mutatedmitochondrial DNAs (mtDNAs) (13,14,25). In this aspect, thecorrect function of mitochondrial quality control and mito-chondrial dynamics appear very much interrelated. In case ofmtDNA mutations, content mixing might paradoxically contrib-ute to the spread of mutated molecules through attenuating aradical selection against nonfunctional mitochondria.

Mitochondrial Formation of ROS andNeurodegenerationIt is commonly accepted that ROS (H2O2, O2

", and OH) play asignificant role in pathogenesis of various neurodegenerativediseases (for comprehensive reviews see (27,28)). Despite theprogress in characterizing ROS effects on lipids (resulting inperoxidation), proteins (resulting in SH-group oxidation andformation of carbonyls), and DNA (formation of 8-OH guano-sine and of single and double strand breaks) (29,30), the par-ticular impact of potential sites relevant for cellular superoxideand hydrogen peroxide generation in brain tissue is less clear.Within the respiratory chain complex I, the FMN moiety(31,32), iron-sulfur clusters (33,34), and semiquinones (35)have been suggested to be responsible for mitochondrialsuperoxide production. For respiratory chain complex III, thesemiquinone at center ‘‘o’’ of the Q-cycle (being stabilized byantimycin A treatment) has been identified as an additionalsite of mitochondrial superoxide production (36), which in con-trast to complex I releases superoxide to the intermembranespace (37,38). While under conditions of inhibited electrontransfer (e.g., under conditions of cytochrome c release), allthese sites are potentially relevant, the relevance of the lattersite under the conditions of uninhibited electron flow is still amatter of discussion (39,40). Additionally to the sites withinmitochondrial respiratory chain, several flavoproteins in themitochondrial matrix space, like the a-lipoamide dehydrogen-ase moiety of the a-ketoglutarate dehydrogenase complex(41,42) or the electron transfer flavoprotein of the b-oxidationpathway (37), are further candidate sites for mitochondrialsuperoxide production.

In brain tissue, apart from the monamine oxidases of outermitochondrial membrane (involved in catecholamine break-down (43)), there exist further potentially relevant ROS pro-ducers, and many of these are located outside of mitochondria.These are plasma membrane NADPH oxidases that are highlyexpressed in astrocytes and oligodendrocytes (44,45), cyto-chromes P450 (46), and even catecholamine derivatives (47).Thus, elevated rates of basal ROS production by catecholaminemetabolism might explain the high loads of mtDNA deletionsobserved in aged substatia nigra neurons (48,49). Additionally,oligodendrocytes and astrocytes contain considerable amountsof peroxisomes, which potentially also could contribute tooverall physiological ROS production in brain tissue. On thecellular level, astroglial cells are considered to contain much

more glutathione than neurons (for review, see (50)), so thatthe additional ROS producers of astroglial cells might be ingeneral less relevant. Also cultured neurons from the cortexcontain considerably less glutathione than astroglial culturesfrom cortex (51). However, it has been demonstrated that theamount of glutathione in neurons and astroglial cells varieswith the brain region from which the cells have been prepared(52), explaining in part the selective vulnerability of certainneuronal populations.

Studies on brain homogenates indicate that #60% of esti-mated maximal ROS production is of mitochondrial origin (40).Under pathological conditions (e.g., in ischemia—reperfusioninjury, in inflammation, etc.), this is highly relevant, becauseinterruption of electron flow through mitochondrial respiratorychain (e.g., by cytochrome c release, modification of electrontransport proteins) would considerably increase superoxidegeneration by all relevant single electron donor sites of dam-aged mitochondria, given enough oxygen is available(32,40,53). Thus, pathological conditions strongly facilitatingROS-mediated oxidative damage of proteins, lipids, and DNAwould require an effective elimination of damaged proteinsbut also damaged mitochondria by the quality control machin-ery discussed above (section ‘‘Mitochondrial Quality Control’’),in order to avoid further cellular damage.

Specific Properties of Neuronal Cell PopulationsAs noted above, difference in glutathione content and differen-ces in expression of ROS producing enzymes might alreadyexplain differences in vulnerability between neurons andastroglial cells. However, considerable differences occur alsobetween individual neuronal populations. As an example, hip-pocampal granular cells are much more resistant to seizure-induced damage than pyramidal cells or interneurons (54).Possible reasons are large differences in mitochondrial con-tent—granular cells contain, in contrast to fast-spiking inter-neurons and principal cells, less mitochondria (55). A highermitochondrial content is very likely related to stronger de-pendency on OxPhos-related ATP production. In turn, thesecells produce upon an injury higher amounts of respiratorychain-dependent ROS and are, therefore, at much higher riskof cellular damage at insults, which explains their increasedvulnerability.

Neurodegenerative Diseases withEvidence for Direct MitochondrialInvolvementCompelling evidence for the direct involvement of mitochon-dria in the pathogenesis of neurodegenerative diseases comesfrom the identification of mutated genes in the inherited formsof these diseases (see Table 1). These include inherited formsof Parkinson’s disease (PD), spinocerebellar ataxias (SCA),HSP, CMT, Huntington’s disease (HD), ALS, OA, and

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Mitochondrial or interacting with mitochondria genes associated with inherited neurodegenerative diseases (modifiedaccording to ref. 56)

Charcot-Marie-Tooth disease (CMT)

CMT1F/2E NEFL Neurofilament, light chain (NFL)

CMT2A1 KIF1B Kinesin 1B

CMT2A2 MFN2a Mitofusin

CMT2D GARS Glycyl-tRNA synthetase

CMT2K/4A GDAP1a Gangloside-induced differentiation-associated protein 1

Spinocerebellar ataxia (SCA)

SCA3 ATXN3a Ataxin-3 deubiquitinase

SCA12 PPP2R2B PP2A regulatory subunit 2B beta

SCA28 AFG3L2a Paraplegin-like AAA protease

SCAN1 TDP1a Tyrosyl-DNA phosphodiesterase 1

SCAR9 ADCK3a Ubiquinone synthesis regulatory kinase (CABC1)

IOSCA c10orf2a Twinkle helicase

MIRAS POLGa Mitochondrial DNA polymerase gamma

FRDA1 FXNa Frataxin

Hereditary spastic paraplegia (HSP)

SPG4 SPAST Spastin

SPG7 SPG7a Paraplegin AAA protease

SPG8 KIAA0196 Strumpellin AAA protease

SPG10 KIF5A Kinesin 5A

SPG13 HSPD1a Heat-shock protein 60 (HSP6C)

SPG20 SPG20 Spartin

SPG31 REEP1 Receptor expression-enhancing protein 1

Parkinson’s disease (PD)

PD NDUFV2a Complex I subunit

PARK1/4 SNCAa Alpha-synuclein

PARK2 PARKINa Parkin

PARK6 PINK1a PTEN-induced protein kinase 1

PARK7 PARK7a DJ-1

PARK11 GIGYF2 GRB10 interacting GYF protein 2

PARK13 HTRA2a HtrA serin peptidase 2 (OMI)

PARK14 PLA2G6 Phospholipase A2, group VI (iPLA2 beta)

TABLE 1

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progressive epilepsy, but not Alzheimer’s disease. However,only several rare forms of these neurodegenerative diseasescan be classified as direct mitochondrial disorders affectingprimarily OxPhos: IOSCA, SCAR9, MIRAS, rare forms of PD,LHON, AHS, MERRF, and MELAS. Apart from maternal inher-ited forms of progressive myoclonic epilepsy which have beenassociated with point mutations in mitochondrial tRNA genes((57); cf. Table 1), only two well proven pathogenic point muta-tions of mtDNA have been reported to be associated with par-kinsonism (58) and spinocerebellar ataxia (59), respectively.One further report, proposing a more general maternal inheri-tance of neurodegenerative disorders (60), remains to be con-firmed by other groups. Nuclear mutations affecting proteinsinvolved in mtDNA replication—the mtDNA polymerase c(POLG) and the helicase Twinkle (c10orf2)—cause progressivemyoclonic epilepsy (61) and rare forms of ataxia (62). Amongrare ataxias, two further disorders have been associateddirectly with oxidative phosphorylation: Friedreich’s ataxia,caused by mutations of frataxin involved in the synthesis ofiron-sulfur proteins (63) and SCAR9, caused by mutations inADCK3, a regulatory protein involved in the synthesis pathwayof coenzyme Q (64). All other neurodegenerative diseasesshow only indirect links to OxPhos, because they affect mito-chondrial dynamics (CMT2A, OPA1, and OPA3) or quality con-trol (SCA28, SPG7, PARK2, PARK6, and PARK7) or related

pathways. Therefore, taken together, neurodegenerative disor-ders cannot be simply classified as mitochondrial cytopathies.Nevertheless, it is important to mention in this respect thatamong the about 100 identified genes so far associated withinherited forms of neurodegenerative disorders, at least 39have some type of association to mitochondrial function (Table1). These genes either code for proteins in known mitochon-drial biochemical pathways or mitochondrial structural pro-teins (27 genes) or for proteins that are not necessarily tar-geted to mitochondria, but that affect them secondarily, likethose involved in the communication between mitochondriaand the ER or involved in mitophagy (12 genes; cf. comprehen-sive review by (56); and Table 1).

Among neurodegenerative diseases, especially geneticforms of PD appear to be closely related to impairment of mi-tochondrial quality control. Recent evidence strongly suggeststhat parkin, a cytosolic E3 ubiquitin ligase, which is mutatedin PARK2, recruits damaged mitochondria by its direct inter-action with PINK1 (65,66) thus initiating their elimination.Accordingly, loss-of-function PINK1 mutations have beendescribed in other forms of inherited parkinsonism: PARK6.Because mitophagy requires the interaction of parkin andPINK1, this explains the PARK2 and PARK6 forms of inheritedparkinsonism as ‘‘nonefficient’’ removal of damaged mitochon-dria in postmitotic neurons. It remains, however, to be

(Continued)

Amyotrophic lateral sclerosis (ALS)

ALS VCPa Valosin-containing protein/p97

ALS1 SOD1a Superoxide dismutase, Cu, Zn-containing

ALS12 OPTN Optineurin

Huntington disease (HD)

HD HTTa Huntingtin

Optic atrophy (OA)

OPA1 OPA1a Dynamin-related GTPase

OPA3 OPA3a Dynamin-related GTPase

OPA7 TMEM126Aa Transmembrane protein 126A

LHON mtDNA (ND1, ND4, ND6)a Complex I subunits (mtDNA encoded)

Progressive epilepsy

AHSb POLGa Mitochondrial DNA polymerase gamma

MERRF mtDNA (tRNA genes)a Mitochondrial tRNAs

MELAS mtDNA tRNA genes)a Mitochondrial tRNAs

a Gene products with confirmed mitochondrial targeting.b Alpers-Huttenlocher syndrome.

TABLE 1

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understood how this mechanism affecting the short-term turn-over of mitochondria by mitophagy is compatible with the wellknown very slow disease progression, as documented by themild phenotypic changes of mice expressing mutant PINK1 (67).An alternative molecular mechanism explaining the slowly pro-gressive mitochondrial dysfunction in dopaminergic neurons issuggested to be related to clonal accumulation of deleted mtDNAmolecules at the single cell level ((48,49); see discussion in fol-lowing section). This in turn would diminish the residual amountof wild-type mtDNA, thus leading to progressive mitochondrialdysfunction by reduced expression of mitochondrially encodedproteins, like certain subunits of respiratory chain. Elevated lev-els of mitochondria with nonfunctional respiratory chains couldperhaps explain elevated levels of intrinsic ROS production (seeabove), affecting in turn mtDNA mutagenesis, as well as the pro-gressive bioenergetic failure of neurons.

Genetic Mechanisms Explaining DiseaseProgressionIn opposite to other biomolecules of the cell, the main functionof DNA does not alone depend on its biochemical properties,but is rather represented by the information stored in it. Dam-aged DNA molecules can undergo different repair processes,which might recover the original state of the DNA, but mightalso result in biochemically intact molecules with altered infor-mation content, that is, mutants (Fig. 2). This property of the

DNA makes it a good candidate to be the molecular basis forlong lasting and accumulating remnants of cell damage.

The most intensively investigated forms of mtDNA muta-tions are large deletions where a substantial part of the mito-chondrial genome is missing. The exact mechanisms of mtDNAdeletion formation are not known. Current hypotheses arebased on properties of previously observed deleted mtDNAmolecules. The fact that deletions have often been observed inthe major arc between the two replication origins of the mito-chondrial genome lead to the assumption that slipped-strandreplication is one of the main sources of mtDNA deletion gen-eration (68). Replication can, however, also play a role in dele-tion formation through inducing double-strand breaks (DSBs).Such damaged mtDNA molecules are generated at sites ofstalled replication (69). If these linear DNA molecules (deletionprecursors) are not eliminated by degradation, repair proc-esses might convert them to intact but incomplete mtDNA mol-ecules (70). The relevance of DSBs in deletion generation wasdemonstrated in a mouse model, where strand breaks wereinduced by expression of a mitochondrially targeted endonu-clease (71). In this model system, many of the deletions had abreakpoint within the D-loop region of the mitochondrial ge-nome, close to the replication-relevant termination associatedsequence (72).

Beside replication stalling, another relevant source ofDSBs is ROS. While nuclear DNA is located in a specializedcell organelle that is dedicated to the organization and protec-tion of the chromosomes, mtDNA is forming nucleoids that areassociated to the inner mitochondrial membrane, one of theenergetically most active spots in the cell. Even normal elec-tron flow through the complexes of the respiratory chain pro-duces a certain amount of ROS, and it can further increase incases of inhibited electron transport (see section ‘‘Mitochon-drial Formation of ROS and Neurodegeneration,’’ (32)). There-fore, mitochondrial respiratory activity very likely plays acentral role in mtDNA damage. The other way around, mtDNAcodes for the key subunits of the respiratory chain, and its bio-synthesis is probably regulated by the energetic needs of thecell. Failure in generating sufficient amounts of functionalmtDNA molecules directly leads to respiratory deficiency. Thisreciprocal connection between mtDNA and mitochondrial res-piration inspired the vicious circle hypothesis of progressivemitochondrial dysfunction (73). However, investigations ofmtDNA alterations at the single cell level suggested that,beside mutagenesis, another process is equally relevant in theprocess of mutation accumulation: replicative segregation ofmutated molecules. Single respiratory deficient neurons insubstantia nigra of patients with PD display high amounts ofsingle mtDNA deletion species, and different neurons arecarrying different deletion species (48,49). This suggests thatthe critical mass of mutated mtDNA molecules within a cell isreached not by repeated mutagenesis but mainly through theclonal expansion of a few mutated molecules. According tocurrent hypotheses, this clonal expansion of deletions might bedue to a replicative advantage of shorter mtDNA molecules

Mechanisms of mutation accumulation in mitochon-drial DNA. Failure in replication of mtDNA and envi-ronmental factors lead to mtDNA damage. Damagedmolecules (indicated by star) are either eliminated orundergo repair processes. Repair might restore theoriginal wild-type state, but it can also lead to bio-chemically intact molecules with altered or partiallylost information content (mutant). Replicative segrega-tion of mutated molecules contributes to the accumu-lation of mutations. BER, base excision repair; MMR,mismatch repair; DSBR, double strand break repair;POLG, mitochondrial DNA polymerase c; ROS, reactiveoxygen species being able to attack mtDNA.

FIG 2

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6 Mitochondrial Involvement in Neurodegenerative Diseases

(74). The time span that is required for this process to resultin functionally significant amount of mutated mtDNA in a cellis estimated to be several decades (75). Interestingly, mito-chondria containing high levels of mutated mtDNA do notalways seem to be eliminated by the quality control pathwaydescribed in section ‘‘Mitochondrial Quality Control.’’ One pos-sible reason for this might be the preservation of the mem-brane potential in mitochondria containing high levels ofmutated mtDNA. Similar to q0 cells that completely lackmtDNA, the reverse action of adenine nucleotide translocaseand proton translocating ATPase can keep in respirationincompetent mitochondria the mitochondrial membrane poten-tial high by using the remaining ATP supply of the cell (pro-duced by glycolysis). This would explain why high levels ofpathogenic mtDNA mutations can easily accumulate in coloncrypts (76) or in skeletal muscle fibers having a high glycolyticactivity. In neurons, which cannot compensate easily the lack-ing ATP supply of oxidative phosphorylation by glycolysis, itappears more likely that mitochondria with high loads of path-ogenic mutations approach a state of decreased membranepotential making them potential targets for quality control on

the organelle level. Nevertheless, mitochondria containinghigh loads of mtDNA mutations tend also to accumulate incertain neurons (49), which might indicate some limitations inthe operation of the mitochondrial quality control system.

The parallel action of mtDNA mutagenesis and replicativeexpansion of mitochondrial mutations is not specific for dis-ease conditions, but it has also been described in normalaging. This raises the question as to what makes the differencebetween normal aging and progressive disease. One possibilityis that insufficient mtDNA maintenance leads to increased rateof mutagenesis or, through decreased copy numbers, toincreased speed of clonal expansion. This is the case in indi-viduals with pathogenic mutations in proteins of mtDNA repli-cation (POLG (77); POLG2 (78); Twinkle (79)), however, dis-eases caused by these mutations often manifest at muchyounger ages than common neurodegenerative diseases. Muta-tions in proteins that affect mitochondrial fusion (MFN2,OPA1) can cause a secondary disturbance of the mtDNA main-tenance probably through the lack of appropriate content mix-ing. Accordingly, decreased mtDNA copy numbers (depletion)and multiple deletions have been observed in individuals with

Hypothetical mechanism of mitochondrial involvement in neurodegeneration. The numbers indicate different groups of genesbeing mutated in inherited forms of neurodegenerative diseases. 1 (maternally transmitted mtDNA mutations): LHON (MT-ND1,MT-ND4, MT-ND6); progressive myoclonic epilepsy (MT-TK, MT-TF, MT-TL1); Leigh syndrome (MT-ATP6); 2 (mutations ingenes affecting mtDNA maintenance): MIRAS and progressive myoclonic epilepsy (POLG); IOSCA (c10orf2); 3 (mutations ingenes affecting mitochondrial fusion and fission): CMT2A2 (MFN2); OPA1 (OPA1); OPA3 (OPA3); 4 (mutations in genes affectionmitochondrial quality control): PARK2 (PARKIN); PARK6 (PINK1); PARK7 (PARK7); SPG7 (SPG7); SCA28 (AFG3L2).

FIG 3

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mutant MFN2 and OPA1 (80–82). Decreased copy numberscorrelate with decreased respiratory enzyme activities, but itis not clear whether the respiratory deficiency plays the cen-tral role in the pathogenesis or rather the disturbed distribu-tion of mitochondria within the neurons. Neurodegenerationassociated with accumulation of clonal mtDNA deletions wasalso described in temporal lobe epilepsy with hippocampussclerosis (54,83). It is hypothesized that oxidative damage ofmtDNA due to febrile seizures in childhood could be the rea-son for increased mutagenesis. A slow clonal expansion ofthese deletions would then lead to respiratory dysfunctions inhippocampal pyramidal neurons and interneurons causing celldeath and intractable chronic epilepsy at adult age (54,84).Clonal expansions of mtDNA deletions have also been observedin patients with multiple sclerosis (MS) and are suggested tobe an important contributor to neurodegeneration in MS(85,86). Here, chronic inflammation appears to trigger mtDNAmutagenesis and initiate clonal expansion.

Figure 3 provides an overview of genetical and physiologi-cal factors whose proposed interplay culminates in accumula-tion of mutated mtDNA, respiratory failure, and insufficientATP supply, affecting neurotransmitter release and leadingfinally to neuronal degeneration.

Final RemarksThe fact that many of the mitochondrial proteins whosemutations have been found to be associated with inherited neu-rodegenerative disorders do not directly affect oxidative phos-phorylation could be interpreted that insufficient neuronal ATPproduction plays only a subordinate role in neurodegeneration.In opposite, we hypothesize that, in case of neurons, local imbal-ances between ATP demand and supply might play a centralrole in the pathogenesis. The effects of altered mitochondrial dy-namics and insufficient quality control are especially dramatic insubcellular compartments that have a high energy demand andthat are located far away from the soma, such as the presynap-tic terminal. Local, rather mild ATP shortages would explainwhy neurodegenerative disorders have a much later age ofonset than typical mitochondrial syndromes with primary failureof the oxidative phosphorylation. On the other hand, the pro-gressive nature of neurodegenerative disorders might alsodepend on the general decline of ATP production in single neu-rons caused by accumulating somatic mtDNA mutations, a pro-cess that is also observed during normal aging. The concertedaction of local ATP insufficiency and the time-dependent clonalexpansion of somatic mtDNA mutations would explain the spe-cific susceptibility of neurons in neurodegenerative disorders.

AcknowledgementsThis work was supported by the Bundesministerium fur Bil-dung und Forschung (mitoNET 01GM0868), the Deutsche For-schungsgemeinschaft (SFB TR3 A11 and D12), and the Stiftungfur Medizinische Wissenschaft, Frankfurt am Main.

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