Mitochondrial Disorders in Neurons 2008

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Mitochondrial Disordersin the Nervous System

Salvatore DiMauro1 and Eric A. Schon1,2

Departments of Neurology1 and Genetics and Development,2 Columbia University MedCenter, New York, NY 10032; email: [email protected], [email protected]

Annu. Rev. Neurosci. 2008. 31:91123

First published online as a Review in Advance onMarch 10, 2008

The Annual Review of Neuroscience is online atneuro.annualreviews.org

This articles doi:10.1146/annurev.neuro.30.051606.094302

Copyright c 2008 by Annual Reviews.All rights reserved

0147-006X/08/0721-0091$20.00

Key Words

mitochondrial DNA, maternal inheritance, oxidative stress, apoptosis

oxidative phosphorylation, aging

Abstract

Mitochondrial diseases (encephalomyopathies) have traditionally been

ascribed to defects of therespiratory chain,whichhas helpedresearcherexplain their genetic and clinical complexity. However, other mitochon

drial functions are greatly important for the nervous system, includingprotein importation, organellar dynamics, and programmed cell death

Defects in genes controlling these functions are attracting increasingattention as causes not only of neurological (and psychiatric) disease

but also of age-related neurodegenerative disorders. After discussingsome pathogenic conundrums regarding the neurological manifestations of the respiratory chain defects, we review altered mitochondria

dynamics in the etiology of specific neurological diseases and in thphysiopathology of more common neurodegenerative disorders.

91

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Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 92

DISEASES OF THEMITOCHONDRIAL

RESPIRATORY CHAIN . . . . . . . . . . 93Disorders Caused by Mutations in

mtDNA . . . . . . . . . . . . . . . . . . . . . . . . 93Disorders Caused by Mutations in

nDNA . . . . . . . . . . . . . . . . . . . . . . . . . 97DISEASES CAUSED BY IMPAIRED

MITOCHONDRIAL PROTEINIMPORT . . . . . . . . . . . . . . . . . . . . . . . . . 103

DISEASES CAUSED BY ABERRANTMITOCHONDRIAL

DYNAMICS . . . . . . . . . . . . . . . . . . . . . . 104AGING AND LATE-ONSET

NEURODEGENERATIVE

DISORDERS . . . . . . . . . . . . . . . . . . . . . 106Mitochondria and

Neurodegeneration . . . . . . . . . . . . . . . . 108Neurodegenerative Diseases Caused by

Mutations in Nuclear-EncodedProteins Targeted

to Mitochondria . . . . . . . . . . . . . . . . . . . 108MITOCHONDRIAL

PSYCHIATRY . . . . . . . . . . . . . . . . . . . . 112CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 113

INTRODUCTION

Mitochondrial dysfunction plays a crucial role

in neurology. This notion became apparentthree decades ago when pediatric neurologists

Table 1 Mitochondrial respiratory chain disease targets

Mutations in mtDNA Mutations in nDNA

R.C. subunits R.C. subunits

Complex I, II, IIIProtein synthesis genes Ancillary proteins

Rearrangements Complex I, III, IV, V; CoQ

tRNAs Intergenomic communication

rRNAs Multiple mtDNA deletions

Depletion of mtDNA

Translation of mt-mRNAs

Mitochondrial lipids

coined the term mitochondrial encephalom

opathies to call attention to the frequent ocurrence of brain disease in children w

mitochondrial alterations in their muscle biosies (Shapira et al. 1977). The selective v

nerability of skeletal muscle and of the n vous system was confirmed in 1988, wh

the first pathogenic mutations in the michondrions own DNA (mtDNA) were disco

ered (Holt et al. 1988, Wallace et al. 198These discoveries heralded the era of michondrial genetics and led to the recogniti

of a multitude of mtDNA-related disordemostly maternally inherited and mostly ma

ifesting as encephalomyopathies (DiMauroDavidzon 2005, DiMauro & Schon 2003). B

cause mtDNA encodes only 13 proteins, of them subunits of the mitochondrial respi

tory chainthe business end in terms of ATproductionanother notionbecame widely

cepted: The term mitochondrial encephalomopathies was reserved for defects of the res

ratory chain.Even within these boundaries, the classifi

tion of the mitochondrial encephalomyopathsoon became quite cumbersome, including tflavors of primary mtDNA mutations (i.e.,

impairment of global mitochondrial protsynthesis andof the translation of specific res

ratory chain subunits) and a much larger meof Mendelian disorders (Table 1). Also, g

netic errors in other fundamental mitochodrial functions that do not affect the respirat

chain directly have major deleterious effects the nervous system, including impaired imp

tation of mitochondrial proteins and defectsmitochondrial dynamics, such as motility, fi

sion, fusion, and distribution.Another topic of current interest is the r

of progressive mitochondrial dysfunction

normal aging and in the pathogenesis of laonset neurodegenerative disorders.In this review, we discuss first the nervo

system disorders caused by mitochondrial r

piratory chain defects, emphasizing how thpathogenesis is still largely terra incognita. W

then consider the burgeoning new group of dorders attributed to defects of mitochondr

92 DiMauro Schon


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dynamics. Last, we review the neurodegenera-

tive disorders in which mitochondrial dysfunc-tion is either primary or seems to be at least

involved in pathogenesis. We do not discussmitochondrial metabolic pathway defects other

than the respiratory chain, such as pyruvate de-hydrogenase complex (PDHC) deficiency or-

oxidation defects, although the nervous systemis frequently affected in those disorders, too.

DISEASES OF THEMITOCHONDRIAL RESPIRATORYCHAIN

These diseases can be caused by mutationsin mtDNA (sporadic or maternally inherited

traits)or by mutations in nuclear DNA(nDNA;Mendelian diseases).

Disorders Caused by Mutationsin mtDNA

Human mtDNA (Figure 1) is a 16.6-kb cir-cular, double-stranded molecule, which con-

tains 37 genes: 2 rRNA genes, 22 tRNA genes,and 13 structural genes encoding subunits of

the mitochondrial respiratory chain (Andersonet al. 1981). Reducing equivalents produced inthe Krebs cycle and in the -oxidation spi-

ral are passed along a series of protein com-plexes embedded in the inner mitochondrial

membrane(theelectron transportchain), whichconsists of four multimeric complexes (I, II,

III, and IV) plus two small electron carriers,coenzyme Q (or ubiquinone) and cytochrome c

(Figure 2). The energy generated by the re-actions of the electron transport chain is used

to pump protons from the mitochondrial ma-trix into the intermembrane space (IMS) lo-

cated between the inner and outer mitochon-

drial membranes. This process creates an elec-trochemical proton gradient, which is utilizedby complex V (or ATP synthase), a tiny rotary

machine that generates ATP as protons flowback into the matrix through its membrane-embedded F0 portion, the rotor of the turbine.

The motors stator (called the F1 portion) pro-trudes into the matrix and converts ADP and

mtDNA:mitochondrial DNA

PDHC: pyruvatedehydrogenasecomplex

nDNA: nuclear DN

inorganic phosphate (Pi) to ATP in a tripartite

series of catalytic reactions [three sets of/

dimeric subunits alter their conformations via

a rotating cam that connects Fo to F1 so asto bind ADP +Pi first, then to convert ADP

and Pi to form ATP, and finally to release theATP into the matrix, where it is exported from

the organelle into the cytoplasm via the adeninenucleotide translocator (ANT)].

At this point, a brief reminder of the rules ofmitochondrial genetics is de rigueur.

1. Heteroplasmy and threshold effect. Each

cell contains hundreds or thousands ofmtDNA copies, which, at cell divi-

sion, distribute randomly among daugh-ter cells. In normal tissues, all mtDNA

molecules are identical (homoplasmy).Deleterious mutations of mtDNA usu-

ally affect some but not all mtDNAs (het-eroplasmy), and the clinical expression of

a pathogenic mtDNA mutation is deter-mined largely by the relative proportions

of normal and mutant genomes in dif-ferent tissues. A minimum critical muta-tion load (typically above 80%90%) is

required to cause mitochondrial dysfunc-tion in a particular organ or tissue and mi-

tochondrial disease in an individual: Thisis the threshold effect.

2. Mitotic segregation. At cell division, theproportion of mutant mtDNAs in daugh-ter cells may shift and the phenotype may

change accordingly. This phenomenon,called mitotic segregation, explains how

the clinical phenotype in patients withmtDNA-related disorders may change as

patients grow older.3. Maternal inheritance. At fertilization, all

mtDNA derives from the oocyte. There-

fore, themode of transmission of mtDNA

and of mtDNA point mutations (singledeletions of mtDNA are usually sporadicevents) differs from Mendelian inheri-tance. A mother carrying a mtDNA point

mutation will pass it on to all her children(males and females), but only the daugh-

ters will transmit it to their progeny.Thus, a disease expressed in both sexes

www.annualreviews.org Mitochondrial Disorders in the Nervous System 93


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HSP

LSP

D-Loop

T

P

E

Cyt b

ND5

ND6

ND4L

KSS

S

A

Q

OL

N

C

Y

ND4

ND3

ND2

ND1

L

V

12 S F

16 S

R

G

COX III

COX II

COX I

W

M

I

D

A6A8K

LS

H

Parkinsonism

LHONDystonia

LS, LHONDystonia

LS, LHON

LS

LSNARPMILSFBSN

MERRF

Epilepsy

Alpers-like

MNDEpilepsy

LS

MELAS

MELAS

OH

Figure 1

The human mitochondrial genome. The mtDNA-encoded gene products for the 12S and 16S ribosomal RNAs, the subunits ofNADH-coenzyme Q oxidoreductase (ND), cytochrome coxidase (COX), cytochrome b (Cyt b), and ATP synthase (A), and 22 tRNA(1-letter amino acid nomenclature) are shown, as are the origins of heavy- and light-strand replication (OH and OL) and the promotof heavy- and light-strand transcription (HSP and LSP). Some pathogenic mutations (for expanded versions of all the key terms in tharticle, see Supplemental Term List; follow the Supplemental Material linkfrom the Annual Reviews home page athttp://www.annualreviews.org) that affect the nervous system in particular are indicated (colors correspond to those of the affected genes

butwithnoevidenceofpaternaltransmis-sion is strongly suggestive of an mtDNApoint mutation.

About 200 mtDNA point mutations andinnumerable single large-scale (kilobase-sized)

partial deletions have been associated with h

man diseases, most of which affect the centandperipheral nervous system, especiallyif m

opathies are consideredas they shouldtdomain of peripheral neurology. This conc

94 DiMauro Schon

Supplemental Material
http://arjournals.annualreviews.org/doi/suppl/10.1146/annurev.neuro.30.051606.094302http://arjournals.annualreviews.org/doi/suppl/10.1146/annurev.neuro.30.051606.094302


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Succinate Fumarate

Diseases

Diseases

LHON

MELAS

LHON + dystonia

Leigh syndrome

Leighsyndrome

Leukodystrophy

Leighsyndrome

Encephalo-myopathy

Leighsyndrome

Cardioencephalo-myopathy

Leukodystrophy/tubulopathy

Fatal infantileencephalomyopathy

Leighsyndrome

Encephalo-myopathy

Nephrosis

NDUFA1

NDUFS1

NDUFS2

NDUFS3

NDUFS4

NDUFS6

NDUFS7

NDUFS8

NDUFV1

NDUFV2

NDUFA12L

SDHA

SDHB

SDHC

SDHD

7 0

4

1 3 2

~39

APTX

COQ2

PDSS1

PDSS2

BCS1L

UQCRB

COX10

COX15

LRPPRC

SCO1

SCO2

SURF1

ATPAF2

ND1 ND6

Encephalomyopathy

Cyt b

ALSlike syndrome

Encephalomyopathy

COX I COX III ATPase 6

NARP

MILS

FBSN

Mutated genes

Mutatedgenes

IMM

IMS

mtDNA-encoded subunits

nDNA-encoded subunits

Matrix

e

e ee

O2

e

H2O

ADP AT

Complex I Complex II Complex III Complex IV Complex V

COX ICOX II

COX III

A8

A6

ND1 ND2ND3

ND4Cyt b

ND6

ND5 ND4L CoQ

Cyt c

10 10 ~16

Figure 2The mitochondrial respiratory chain (RC), showing nDNA-encoded subunits (blue) and mtDNA-encoded subunits (colors correspondinto the genes in the map in Figure 1). Protons are pumped from the matrix to the intermembrane space through complexes I, III, and IVand are pumped back to the matrix through complex V to produce ATP. Coenzyme Q and cytochrome care electron (e) transfercarriers. Diseases (see Supplemental Term List) caused by mutations in mtDNA (above the RC) and in nDNA (below the RC) arelisted according to the correspondingly affected RC complex. Genes in bold encode RC subunits; those in plain text encode ancillary assembly proteins.

is illustrated in Figure 1 and, in more de-tail, in Table 2, which highlights the typical

clinical features of the five most commonmtDNA-related syndromes of neurological in-

terest.Thesearenotdescribedhere in anymoredetail because the features can be found in text-

book reviews (Hays et al. 2006, Hirano et al.2006a).

The human mitochondrial genome is satu-rated with mutations. Does this mean that weare scraping the bottom of the barrel as far

as our understanding of mtDNA-related dis-eases is concerned? Not by a long stretch. Al-

though, understandably, the pace at which newpathogenic mutations are discovered has slack-

ened in recent years, novel mutations are stillbeing reported, and several questions still awaitanswers in the field of mitochondrial genetics.

For example, whereas mostpathogenicmtDNAmutations are heteroplasmic and clinical sever-

ity is usually relatedto mutation load, some mu-tations are homoplasmic, and yet the severity


Supplementa
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Table 2 Clinical features in diseases associated with mtDNA mutations

-mtDNA tRNA ATPase6

TISSUE SYMPTOM/SIGN KSS MERRF MELAS NARP M

of the syndromes they cause differs in different

families or even in members of the same fam-ily. A related question concerns the functionalsignificance of mtDNA haplotypes. In the mi-

gration out of Africa, human beings have accu-mulated distinctive variationson the mtDNA of

the ancestral mitochondrial Eve, resulting inseveral haplotypes characteristic of different

ethnic groups (Wallace et al. 1999). Differ-ent mtDNA haplotypes may modulate oxida-

tive phosphorylation, thus influencingthe over-all physiology of individuals and predisposing

them toor protecting them fromcertaindiseases (Carelli et al. 2006). Clearly, much

work remains to be done to define better boththe pathogenic role of homoplasmic mutations

and the modulatory role of haplotypes in hea

and disease.A major problem in mtDNA-related neu

logical diseases is our woeful ignorance abo

genotype-phenotype correlations. In fact, isurprising that mtDNA mutations should ca

different syndromes in the first place. If,conventional wisdom dictates, both large-sc

mtDNA rearrangements and point mutatioin rRNA or tRNA genes impair mitochondr

protein synthesis and ATP production, it wobe logical to expect a clinical swamp of

defined andoverlapping symptoms andsignsoriginally predicted by the lumpers (Rowla

1994). Although clinical overlap does occurmtDNA-related diseases, it is fair to say th

96 DiMauro Schon


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the splitters won the day, in that most muta-

tions result in well-defined syndromes, includ-ing mutations associated with KSS/PEO, DAD,

MERRF, MELAS, NARP/MILS, LHON, andSNHL.

To explain the distinctive brain symp-toms in patients with KSS, MERRF, and

MELAS, the different mutations have beenmapped indirectly through immunohisto-

chemical techniques. Consistent with clin-ical symptoms and laboratory data, im-munohistochemical evidence suggests that the

mtDNA deletion (-mtDNA) of KSS aboundsin the choroid plexus (Tanji et al. 2000)

(Figure 3ad), the 3243-MELAS mutationis abundant in the walls of cerebral arteri-

oles (Betts et al. 2006) (Figure 3ef), andthe 8344-MERRF mutation is abundant in

the olivary nucleus of the cerebellum (Tanjiet al. 2001) (Figure 3gj). Direct evidence

of the accumulation of -mtDNA in thechoroid plexus of KSS patients was provided

by Tanji et al. (2000) using in situ hybridization(Figure 4). However, these data fail to explain

what directs each mutation to a particular areaof the brain, how the mutation correlates withthe clinical syndrome, or why the syndromes

differ from each other. That mutations in different tRNA genes

may have different mechanisms of action is sug-gested by the apparently selective tissue vul-

nerability associated with mutations in sometRNAs: For example, cardiomyopathy is often

associated with mutations in tRNAIle, diabetesis a frequent manifestation of theT14709C mu-

tation in tRNAGlu, and multiple lipomas havebeen reported only in patients with mutations

in tRNALys. However these are mere associa-tions,not explanations. It is fair to conclude that

the pathogenesis of mtDNA-related disordersis still largely unexplained.

Disorders Caused by Mutationsin nDNA

During the many millennia of symbiotic re-

lation with the nDNA, the mtDNA has lostmore than 99% of its original genes and most

a b

c d

e f

g h

i j

COX II

Control

KSS

Control

MERRF

MELAS

FES

Figure 3

Immunohistochemistry to detect the mtDNA-encoded COX II subunit ofcomplex IV (left panels) and the nDNA-encoded FeS subunit of complex III(right panels) in brain structures in three mtDNA-related diseases. Choroidplexus from a control (A, B) and a KSS patient (C, D). Sub-pial arterioles froa MELAS patient (E, F). Olivary nucleus from a control (G, H) and a MERRpatient (I, J). Courtesy of Drs. Eduardo Bonilla and Kurenai Tanji, ColumbiaUniversity Medical Center.



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Probe 1

Probe 1

wt-mtDNA

Normal

KSS

-mtDNA Deletion

Probe 2

Probe 2

a

b

Figure 4

In-situ hybridization to detect mtDNAs in the choroid plexus from a KSSpatient. (a) Map of wt- and -mtDNAs from the patient showing the twoprobes: Probe 1 (red) detects both wt- and -mtDNAs; probe 2 (blue) detectsonly wt-mtDNA. (b) As opposed to the uniform signal with both probes in thecontrol (upper panels), there is a much stronger signal in the patient with probe1 than with probe 2 (lower panels), indicating a massive accumulation of-mtDNAs. Courtesy of Drs. Eduardo Bonilla and Kurenai Tanji, ColumbiaUniversity Medical Center.

of its autonomy, and it now depends on nuclearfactorsforallitsbasicfunctions,includingrepli-

cation, translation, synthesis of most respira-tory chain subunits, and assembly of respira-

tory chain complexes, and for the synthesisof the phospholipids that constitute the inner

mitochondrial membrane (IMM). This is whythe Mendelian defects of the respiratory chain

can be divided into at least four subgrou

(Table 1).

Mutations in genes encoding respirat

chain subunits. These mutations (direct hhave been found predominantly in the first t

complexes of the respiratory chain, sugge

ing that deleterious mutations in the termincomplexes are either rare or incompatible w

life. One explanation suggests that complexeand II are in parallel, allowing for some res

ual electron transport even when one compis out of commission, whereas complexes I

IV, and V are in series (Figure 2). Althoudirect hits do occur in the mtDNA-encod

subunits of complexes III (cytochrome b), (COX I, II, or III), and V (ATPase 6), the h

eroplasmic nature of these mutations may p

mit some residual activity. However, the ries/parallel hypothesis has been undercutthe finding of a homozygous frameshift mu

tion in the ubiquinone-binding subunit of coplex III UQCRB (Haut et al. 2003), which is

cated at the C-terminus of the protein and sallows for some residual complex III activiIt is more difficult to explain why severe CO

deficiency with recessive mutations in assemproteins (for example SCO2) is still compati

with life, albeit a very abbreviated life.

Most mutations in nDNA-encoded coplex I or in complex II subunits cause Leisyndrome (LS) (Table 3). The hallm

neuropathological lesions of this devastatneurodegenerative disorder of infancy or ea

Table 3 Causes of Leigh syndromea

Defect Transmission Frequency

Complex I AR, M +++

Complex II AR +

Complex IV AR +++

Complex V M ++tRNALeu(UUR) M +

tRNALys M +

CoQ10 AR +

PDHC XR, AR +++

aAbbreviations: AR, autosomal recessive; M, maternal;

X, X-linked.

98 DiMauro Schon


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ba

Figure 5

Typical brain lesionsLeigh syndrome.(a) Coronal sectionshowing bilateral

symmetrical cavitatinlesions in the basalganglia (arrows).(b) T2-weighted MRshowing abnormalbilateral symmetricahyperintense signalsthe lenticular nuclei(arrowheads).

childhood [bilaterally symmetrical foci of cys-tic cavitation (Figure 5), vascular proliferation,

neuronal loss, and demyelination in the basal

ganglia, brainstem, and posterior columns ofthe spinal cord] probably reflect the stereo-typical ravages caused by defective oxidative

metabolism on the developing nervous system.This concept is supported by the observationthat LS is also caused by mtDNA mutations

when they are sufficiently abundant (MILS;Table 2) or severe enough to impair oxidative

phosphorylation early in life (Kirby et al. 2003,Sarzi et al. 2007, Tatuch et al. 1992).

Although some mutations in mtDNA com-

plex I genes cause LS, most do not, butrather cause Leber hereditary optic neuropathy(LHON), a maternally inherited optic atrophy

that causes blindness in young adults with chal-lenging contradictions. First, all pathogenic

LHON mutations are in complex I genes, and yet the complex I deficiency is not particu-

larly severe. Second, whereas some LHONmutations are heteroplasmic (as in most mi-

tochondrial diseases), most are homoplasmic,and yet the pathology is confined, on the

whole, to the retinal ganglion cells (Carelliet al. 2007). Third, even though the mu-tation is often homoplasmic, the blindness

usually does not occur until the patient isolder than age 20, and then each eye is af-

fected sequentially within months. Fourth, al-though LHON is maternally inherited, men

KSS: Kearns-Sayresyndrome

PEO: progressiveexternalophthalmoplegia

MERRF: Myoclonuepilepsy ragged-redfibers

MELAS:mitochondrialencephalomyopathy,lactic acidosis, andstrokelike episodes

NARP: Neuropathyataxia, retinitispigmentosa

LS: Leigh syndromMILS: Maternallyinherited Leighsyndrome

LHON: Leberhereditary opticneuropathy

are affected far more frequently, and moreseverely, than are women, implying an X-linked

modifier effect (Hudson et al. 2005). Also,

rarely, the blindness is partially reversible.

Mutations in genes encoding ancillary pro-

teins. This group of disorders is caused by in-direct hits, that is, mutations in proteins that

are not part of any complex but are neededto synthesize and direct the proper assembly

of the various nDNA- and mtDNA-encodedsubunits, together with their prosthetic groups.

Important clues to the molecular etiology of

these disorders, and especially COX deficiency,came from yeast genetics because most genesneeded for COX assembly in yeast have hu-

man homologues. Another shortcut to find-ing mutant genes without sequencing multiple

candidate COX-assembly genes was the searchfor complementation in COX-deficient cul-

turedcells from patients via monochromosomalhybrid fusion or microcell-mediated chromo-

some transfer, which led to the identification ofthe most common gene responsible for COX-

deficient LS, SURF1 (Tiranti et al. 1998, Zhuet al. 1998). Integrative genomics, on the basisof information derived from DNA, mRNA, and

proteomics studies, led to the identification ofLRPPRC, the gene responsible for LS-French-

Canadian type (LSFC), another COX-deficientform of LS associated with liver diseases and



10/35

prevalent in the Saguenay-Lac Saint-Jean re-

gionof Quebec (Mootha et al. 2003, Morin etal.1993). A bioinformatics approach was also used

to identify the first mutant assembly gene re-sponsible for complex I deficiency,NDUFA12L

(formerly called B17.2L), in a child with severecavitating leukoencephalopathy (Ogilvie et al.

2005). Knowledge of the molecular defects inthese fatal infantile neurological disorders of-

fers young parents who have lost one child theoption of prenatal diagnosis.

Primary coenzyme Q10 (CoQ10) deficiency

encompasses disorders caused by blocks in thebiosynthetic pathway of this small ubiquinone

carrier. CoQ10 transfers electrons from com-plexes I and II to complex III and receives

electrons from the -oxidation pathway

the electron transfer flavoprotein dehydrognase (ETF-DH) (Figure 6). Mutations in t

CoQ10 biosynthetic enzymes (in the PDSand PDSS2 subunits of of COQ1, and

COQ2) have been identified in infants or chdren with encephalomyopathy (one of them h

LS)and nephrotic syndrome (Lopez et al. 20Mollet et al. 2007, Quinzii et al. 2006). Becau

at least nine enzymes are needed to synthsize CoQ10, mutations in the other seven ezymes will probably also be associated with e

cephalomyopathic syndromes (DiMauro et2007). Several syndromes have also been

sociated with a presumed secondary CoQdeficiency. These include autosomal recess

Pyruvate

PDHC

Acetyl-CoA -oxidation

Fatty acids

Krebs cycle

OMM

IMS

IMM

Matrix

ND1 ND2

ND4Cyt b

COX ICOX II

COX III

A8ND6

ND5 ND4L CoQ

Cyt c

A6

ND3

SDH

ETF-DH

ETF

Figure 6

Schematic of mitochondrial intermediate metabolism showing the relationships between pyruvate and fatty acid metabolism and ATsynthesis. Note that the electron-transfer flavoprotein (ETF) delivers electrons from the -oxidation pathway to CoQ10 via theETF-dehydrogenase (ETF-DH).

100 DiMauro Schon


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cerebellar ataxia of unknown etiology in chil-

dren, the syndrome of ataxia and oculomo-tor apraxia (AOA1) caused by mutations in the

aprataxin gene (APTX) (Quinzii et al. 2005),and a predominantly myopathic form of glu-

taric aciduria type II (GAII) caused by muta-tions in the electron transfer flavoprotein dehy-

drogenase gene (ETFDH) (Gempel et al. 2007)(Figure 6). Aside from its scientificimportance,

knowledge of CoQ10 deficiency syndromes isimportant for physicians because most patientsimprove with CoQ10 supplementation.

The other respiratory complexes obviouslyalso require assembly, and mutations in assem-

bly factor BCS1L for complex III (Visapaa et al.2002) and ATPAF2 for complex V (De Meirleir

et al. 2004) have also been found. Clearly, thepool of available candidate genes has yet to be

exhausted (DiMauro & Hirano 2005).

Defects of intergenomic communication.

The alterations of mtDNA of some disor-

ders are not caused by primary mutations ofthe mitochondrial genome, but rather are theresult of garbled messages from the nuclear

genome, which controls mtDNA replication,

maintenance, and translation. The resultingMendelian disorders are characterized by qual-

itative (multiple deletions) or quantitative (de-pletion) alterations of mtDNA, or by defec-

tive translation of mtDNA-encoded respiratorychain components. Of note, most of these dis-

orders are caused by alterations in the pools ofnucleotides required to synthesize mtDNA, orin enzymes associated with mtDNA replication

itself (Spinazzola & Zeviani 2005) (Figure 7).

Multiple mtDNA deletions. From the clini-cal point of view, multiple mtDNA deletion

syndromes share the cardinal features of oc-ular and limb myopathy (PEO, ptosis, prox-

imal weakness), which are almost invariablyassociated with extramuscular system involve-

ment, including peripheral nerves (sensorimo-tor neuropathy), the brain (ataxia, dementia,

psychosis), the ear (sensorineural hearing loss),and the eye (cataracts). Mutations in sev-eral genes, all involved in the homeostasis of

the mitochondrial nucleotide pools, have beenassociated with PEO and multiple mtDNA

dA dAMPdGMP

dADPdGDP

dATP

mtDNA

PEO1,

POLG,

POLG2

NME4, NME6

SUCLA2, SUCLG1AK2, UCK

dGTPDGUOK

dG

dC dCMPdTMP

dCDPdTDP

dCTPdTTP

ADP

ATPdNTPdNDPrNDP

TK2

RRM2B

ANT1

NT5MdT

IMM

OMM

IMS

dAdG

ETN1

Thymine

dCdT

TP

Figure 7

Schematic of nucleotide metabolism for mtDNA synthesis and replication. Genes in bold have been associated with diseasescharacterized by multiple mtDNA deletions and/or with mtDNA depletion.



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MNGIE:mitochondrialneurogastrointestinalencephalomyopathy

deletions. These include ANT1, which en-

codes the adenosine nucleoside translocator;PEO1, which encodes a helicase called Twinkle;

ECGF1, which encodes the cytosolic enzymethymidine phosphorylase (TP); POLG, which

encodes the mitochondrial polymerase cat-alytic subunit; and POLG2, which encodes the

dimeric accessory subunit of POLG (Spinaz-zola & Zeviani 2005). Two of these disorders

are of special interest to neurologists.The first is MNGIE (mitochondrial neuro-

gastrointestinal encephalomyopathy), an auto-

somal recessive multisystem disease of youngadults caused by mutations in TP (Nishino

et al. 1999) andcharacterized clinically by PEO,neuropathy, leukoencephalopathy, and intesti-

nal dysmotility leading to cachexia and earlydeath. Thelack of TP activity damages mtDNA

synthesis, causing not only multiple deletions,but also depletion and point mutations, which

are evident in skeletal muscle, although mus-cle expresses little TP (Hirano et al. 2005).

This muscle paradox suggests that TP defi-ciency acts through toxic intermediates. Two

such toxic intermediates, thymidine and de-oxyuridine, accumulate massively in the bloodof MNGIE patients. Hemodialysis, an obvious

therapeutic approach, has only transient effects,as do platelet infusions, but allogeneic bone

marrow transplantation in one patient restoredTP activity in buffy coat cells and normalized

blood levels of thymidine and deoxyuridine. Al-thoughthe patient hasimproved subjectively 18

months after the procedure, clinical efficacy re-mains to be firmly documented (Hirano et al.

2006b).Disorders associated with mutations in

POLG are inherited as either autosomal-recessive or autosomal-dominant traits. Both

forms of inheritance are encountered in adults

with PEO and multiple mtDNA deletions:Clinical manifestations include ataxia, periph-eral neuropathy, parkinsonism, psychiatric dis-orders, myoclonus epilepsy, and gastrointesti-

nal symptoms (DiMauro et al. 2006a). Autoso-mal recessive inheritance of mutations in POLG

is the rule in children with Alpers syndrome,a severe hepatocerebral disease associated with

mtDNA depletion and extreme vulnerability

valproate administration (Naviaux & Nguy2004). This clinical heterogeneity can, at le

in part, be attributed to the site of the mution in the catalytic subunit, which has a po

merase (i.e., replicating) domain and an exonclease (i.e., proofreading) domain joined b

linker region: Most patients with Alpers sydrome have at least one mutation in the linregion and another in the polymerase doma

whereas adults with PEO tend to have mutions solely in the polymerase domain. To co

plicate matters further, mutations in the dimeaccessory subunit POLG2,which is responsi

for processive DNA synthesis and tight bining of the POLG complex to DNA, can a

cause autosomal dominant PEO (Longley et2006).

Depletion of mtDNA. We have seen h

some mutations in POLG predominantly camtDNA depletion and result in a severe infatile hepatocerebral disorder (Alpers syndrom

In fact, mutations in other proteins contrling the mitochondrial nucleotide pool a

cause mtDNA depletion. For reasons that not completely clear, the degree of depleti

varies in different tissues, but two major sydromes have emerged: (a) hepatocerebral sy

drome, caused by mutation either in POLGin DGUOK, which encodes the enzyme d

oxyguanosine kinase (dGK); and (b) a puror predominantly myopathic syndrome asso

ated with mutations in TK2, which encodes tmitochondrial form of the enzyme thymid

kinase, with mutations in SUCLA2, encodthe subunit of the mitochondrial matrix e

zyme succinyl-CoA synthetase (Elpeleg et2005), and with mutations in RRM2B, encoing the cytosolic p53-inducible ribonucleot

reductase small subunit (p53R2) (Bourdon et2007). However, not all cases of mtDNA d

pletion are explained by mutations in thfour genes, and not all mutated genes are

volved in nucleotide pool homeostasis. For ample, some children with hepatocerebral sy

drome harbored pathogenic mutations in a geon chromosome 2, MPV17, which encodes

102 DiMauro Schon


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IMM protein of unknown function (Spinazzola

et al. 2006). The importance of this gene wasbolstered by the finding that the same homozy-

gous mutation encountered in a southern Ital-ianfamilyisthecauseofadiseaseendemicinthe

Navajo population of the American southwest(Karadimas et al. 2006). The disease is called

Navajo neurohepatopathy (NNH) to stress thatneuropathy rather than encephalopathy accom-

panies the liver dysfunction in this condition,probably because of some as-yet-unknown ge-netic modifier. We can now provide sound ge-

netic counseling to the Navajo population inthe hopes of eradicating this dreadful disease.

Defects of mtDNA translation. Faithful trans-

lation of the 13 mtDNA-encoded subunits ofthe respiratory chain requires not only intact

mtDNA, a trustworthy polymerase, and theavailability of nucleotide building blocks, but

also ribosomal proteins, RNA modificationenzymes, and initiation, elongation, and termi-

nation factors, all encoded by nDNA. Defectsin mtDNA translation result in severe com-

bined respiratory chain complex defects, and itis important to think of this pathogenic mecha-nism in infants or children with hepatocerebral

syndrome, encephalopathy, infantile cavitatingleukoencephalopathy, or cardiomyopathy and

otherwise unexplained multiple respiratorychain defects. Thus far, investigators have

described mutations in four genes, but thisnumber will certainly increase in the years

to come. The first gene, GFM1, encodes oneof four ribosomal elongation factors (Coenen

et al. 2004, Valente et al. 2007); the second,MRPS16, encodes the mitochondrial riboso-

mal protein subunit 16 (Miller et al. 2004);the third, TSFM, encodes the mitochondrial

elongation factor EFTs (Smeitink et al. 2006);

and the fourth gene, TUFM, encodes theelongation factor Tu (Valente et al. 2007). Adifferent syndrome is caused by defective pseu-douridylation of mitochondrial tRNAs and is

characterized by myopathy, lactic acidosis, andsideroblastic anemia (MLASA): Mutations in

this gene, PUS1, which encodes the mitochon-drial enzyme pseudouridine synthase 1, have

been identified in three families (Bykhovskaya

et al. 2004, Fernandez-Vizarra et al. 2006).

Mutations affecting the lipid milieu of the

respiratory chain. The complexes of the res-

piratory chain are embedded in the lipid milieuof the IMM, whose major component is cardi-

olipin, an acidic phospholipid. Cardiolipin doesnot have merely a scaffolding function, but alsoparticipates in the formation of supercomplexes

(stoichiometric assemblies of individual respi-ratory chain complexes into functional units)

(Zhang et al. 2005b) and interacts directly withCOX(Sedlak et al. 2006); conversely, intact res-

piratory chain function is essential for cardi-olipin biosynthesis (Gohil et al. 2004). There-

fore, genetic abnormalities of cardiolipin couldimpair respiratory chain function in humans.

The best candidate for this role is Barth syn-drome, an X-linked recessive disorder charac-

terized by mitochondrial myopathy, cardiomy-opathy, and growth retardation, and caused by

mutations in the gene encoding a phospholipidacyltransferase called tafazzin (TAZ) (Schlame& Ren 2006). Tafazzin promotes structural uni-

formity and molecular symmetry among cardi-olipin molecular species, and mutations in TAZ

alter the concentration and composition of car-diolipin, leading to altered mitochondrial ar-

chitecture and function. Some TAZmutationscause mislocalization of cardiolipin from the

outer mitochondrial membrane (OMM) andIMM to the mitochondrial matrix (Claypool

et al. 2006).

DISEASES CAUSED BYIMPAIRED MITOCHONDRIALPROTEIN IMPORT

Of the 1300+ proteins found in mammalian

mitochondria (Schon 2007), only 13 areencoded by mtDNA. All others are encodedby nDNA genes, synthesized in the cytoplasm,

and imported into the organelle. Mitochon-drial import is a complex process, with differentpathways for protein targeting and sorting to

each of the four mitochondrial compartments(OMM, IMM, IMS, and the matrix enveloped



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HSP: hereditaryspastic paraplegia

SPG: spasticparaplegia

by the IMM). Among the components of the

import machinery, composed of nearly 60polypeptides, are members of the heat shock

protein (HSP) family, chaperones needed forthe unfolding and refolding of mitochondrially

targeted proteins as they transit throughthe import receptors and are directed to the

appropriate compartment. Most, but notall, mitochondrial proteins (especially those

destined for the IMM and the matrix) havewell-defined targeting signals, usually locatedat the N-terminus of the protein. Once inside

the mitochondrion, the mitochondrial target-ing signal (MTS, or leader peptide) is cleaved

to release the mature protein. The importmachinery consists of polymeric translocases

in the outer membrane (TOM) or the innermembrane (TIM). In collaboration with a

sorting and assembly machinery (SAM), apresequence translocation-associated motor

(PAM), and a mitochondrial import and assem-bly (MIA) pathway specific for a subset of IMS

proteins (Gabriel et al. 2006), TOM and TIMsort out incoming polypeptides to the proper

compartments (Chacinska & Rehling 2004).Although a few mutations in leader peptides

have been associated with specific enzyme de-

fects, such as methylmalonic acidemia (Ledleyet al. 1990) and PDHC deficiency (Takakubo

et al. 1995), remarkably few human diseaseshave been attributed to genetic defects of the

general importation machinery. One of theseis an X-linked recessive deafness-dystonia syn-

drome (Mohr-Tranebjaerg syndrome) causedby mutations in the gene (TIMM8A) encoding

the deafness/dystonia protein (DDP), an MIApathway protein located in the IMS (Roesch

et al. 2002). Another is an autosomal dom-inant form of hereditary spastic paraplegia

(HSP type 13; SPG13) caused by mutations in

the import chaperonin HSP60 (Hansen et al.2002).Unless most disorders caused by disruption

of the general importation machinery are in-

compatible with life, as suggested by Fenton(1995), we can expect more such disorders to

be identified in the near future.

DISEASES CAUSED BY ABERRANMITOCHONDRIAL DYNAMICSThis relatively new area of interest for cli

cal neuroscientists has already yielded instrutive results and is sure to provide many mo

in the coming years. Remembering their bacrial origin, mitochondria move, fuse, and div

within cells, where they often form tubular nworks that may favor the delivery of organel

to areas of high energy demand (Bossy-Wetet al. 2003). The need for mitochondrial mo

ity is nowhere more evident than in motor nrons of the anterior horn cells, where mi

chondria must travel a huge distance from tcell soma to the neuromuscular junction. Michondria travel on microtubular rails, propel

by motor proteins, usually GTPases, called nesins (when mitochondria travel downstrea

or dyneins (when they travel upstream). Tfirst mitochondrial motility defect was iden

fiedin a family with autosomaldominant hereitary spastic paraplegia type 10 (SPG10) a

mutations in a gene encoding one of the nesins (KIF5A): The mutation affects a regi

of the protein involved in microtubule bindi(Fichera et al. 2004) (Figure 8).

In yeast, at least four proteins are requirfor mitochondrial fission: Dnm1p (dynam

related protein), Fis1p (fission-related prote

Mdv1p (mitochondrial division protein), aCaf4p (carbon catabolite repression-associa

factor). Of the four, only Fis1p is an integpart of mitochondria, located in theouter me

brane. Upon a signal to divide, Fis1p recruDnm1p to the organelle via the bridge protei

Mdv1p and Caf4p; Dnm1p then forms an evtightening spiral collar around the organe

which severs the mitochondrion by stranglation (Chan 2006). For the opposite proc

of mitochondrial fusion, two proteins are

quired in yeast: Fzo1p (the yeast homologthe Drosophila fuzzy onion protein) and Ugo(ugo is Japanese for fusion). For fission to o

cur, the OMM and IMM must establish cotact sites, apparently through the action of

another protein called Mgm1p (mitochondrgenome maintenance protein 1).

104 DiMauro Schon


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AtlastinSPG3A

SpastinSPG4

SpastinSPG4

Dynein/dynactin

DYNCL1LI2

HAP1

Kinesins

Milton

MFN1 MFN2

CMT6CMT2A

Miro

HTTHD

DNCH1

DISC1SCZD KIF5A

SPG10SynucleinFPD

PARKINFPD

LRRK2FPD

PINK1FPD

DJ-1FPD

HSPD1SPG13

HTRA2FPD

GDAP1CMT4A

Para-pleginSPG7

OPA1(large)DOA

YWHAEMDS

NUDEL

YWHAZ

AFG3L1AFG3L2

PARLOPA1(small)DOA

IMM

Microtubule

Cytosol

OMM

IMS

Matrix

Figure 8

Selected genes associated with mitochondrial dynamics. Genes boxed in yellow have been associated with neurodegenerative orpsychiatric diseases (disease abbreviations in red). Mitochondrially targeted gene products are in bold. Black dots denote reportedinteractions between proteins.

Mutations in the human orthologs ofMgm1p (OPA1) and Fzo1p (MFN2 or mito-

fusin 2) have been associated with human dis-eases. Mutations in OPA1 cause autosomal

dominant optic atrophy (DOA), the Mendeliancounterpart, as it were, of LHON and are char-

acterized by maldistribution of mitochondriain affected cells (Alexander et al. 2000, Delet-tre et al. 2000). Notably, OPA1 interacts with

mitofusin1(MFN1)topromotefusion(Cipolatet al. 2004). However, beyond its role in fusion,

OPA1, an IMM protein, is also required for re-modeling the cristae (Cipolat et al. 2006) to-

gether with PARL (presenilin-associated rhom-boid like), an IMS-localized protein (Pellegrini

& Scorrano 2007). Mutations in the second mitofusin gene,

MFN2, cause an autosomal dominant axonalvariant of Charcot-Marie-Tooth disease (CMT

type 2A) (Lawson et al. 2005, Zuchner et al.2004). A recent review of 62 unrelated axonal

CMT families revealed MFN2 mutations in 26patients from 15 families, which suggests that

this is a major cause of axonal CMT2A (Chung

CMT: Charcot-MaTooth

et al. 2006). In addition, mutations in GDAP1,the gene encoding ganglioside-induced differ-

entiation protein 1, which is located in theOMM and which regulates the mitochondrial

network (Niemann et al. 2005), cause CMTtype 4A, an autosomal recessive, severe, early-

onset form of either demyelinating or axonalneuropathy (Pedrola et al. 2005) (Figure 8).

A remarkable example of the underlying

connections between mitochondrial movementand ostensibly disparate diseases is Charcot-

Marie-Tooth disease type 6 (CMT6), which ischaracterized by the coexistence of peripheral

neuropathy and optic atrophy. Moreover, op-tic atrophy onset is followed in many patients

by slow vision recovery, as sometimes seen inLHON patients. Suchner et al. (2006a) found

mutations in MFN2 in affected members of sixunrelated families with CMT6; one of them

had a missense mutation (R94W) identical tothat in some patients with CMT2A. An un-

derlying problem in mitochondrial movementpresumably causes both peripheral and optic

neuropathy, even though most patients with



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MFN2 mutations do not have optic atrophy,

and most patients with OPA1 mutations do nothave CMT. The patients nuclear background

may influence the penetrance of the mitochon-drial trafficking defect.

Because mitochondria are not the only car-goes to be moved around the cell, it is not

too surprising that mutations in genes con-trolling mitochondrial motility may also affect

other organelles. Both mitochondria and per-oxisomes had abnormal size, shape, and distri-bution in fibroblasts from an infant with a syn-

drome of encephalopathy, optic atrophy, lacticacidosis, and a heterozygous dominant muta-

tion in the human ortholog of yeast Dnm1pcalleddynamin-like or dynamin-relatedprotein

1 (DLP1/DRP1; gene DNM1L) (Waterhamet al. 2007).

A mitochondrial import defect may berelated to impaired neuronal migration

(Figure 8). Two neuronal migration disorders,isolated lissencephaly sequence (ILS) and

the Miller-Dieker syndrome (MDS), areassociated with deletions on chromosome

17p13.3. Mutations in LIS1 (gene PAFAH1B1)cause ILS, whereas a second gene at thislocus, encoding the 14-3-3 protein isoform

(YWHAE), is invariably deleted in patients with MDS lissencephaly (Toyo-oka et al. 2003).

YWHAE is a cytoplasmic chaperone thattargets precursor proteins to the mitochondria,

which is why it is also called the mitochondrialimport stimulating factor subunit L (MSFL)

(Alam et al. 1994). YWHAE interacts withthree other proteins that not only are required

for neuronal migration but also are known toassociate with mitochondria: NUDEL (nuclear

distribution protein nudE-like 1) (Brandonet al. 2005, Ikuta et al. 2007), FEZ1 (fascicula-

tion and elongation protein zeta-1) (Ikuta et al.

2007), and DISC1 (deleted in schizophrenia 1)(Millar et al. 2005). NUDEL targets dynein tomicrotubule ends through LIS1 (Li et al. 2005),whereas altered expression of both FEZ1 and

DISC1 caused mitochondrial morphologyand mobility defects (Ikuta et al. 2007, Millar

et al. 2005). In yeast, the homolog of humanYWHAE (Bmh1p; 14-3-3) interacts with

the homolog of human YWHAZ (Bmh

14-3-3) (Chaudhri et al. 2003); YWHAZin fact, present in mitochondria (Schind

et al. 2006, Taylor et al. 2003). Thus, lossYWHAE may well affect neuronal migrati

either by disrupting the trafficking of these lter proteins to mitochondria or by interdicti

the binding of mitochondria to dynein.These diseases are only the proverbial tip

what will be found to be an iceberg of hum

neurodegenerative disorders directly or inrectly linked to abnormal mitochondrial mo

ity, fusion, or fission (Table 4).

AGING AND LATE-ONSETNEURODEGENERATIVEDISORDERS

In the title of a 1992 News & Viewsarticle Nature Genetics, the late Anita Harding posi

the role of mitochondria in normal aging wher usual wit: Growing Old: The Most Co

mon Mitochondrial Disease of All? (Hardi1992). Her comments concernedan article d

umenting the age-related accumulation of common 4977-bp mtDNA deletion (Sch

et al. 1989) in human brain, but especiain the caudate, putamen, and substantia nig(Soong et al. 1992). Last year, using more

phisticated techniques (laser microdissectiosingle-molecule PCR, long-range PCR), t

groups confirmed the age-related accumution of somatic and clonal mtDNA deletio

in substantia nigra and showed that neurowith high mutation loads were COX-negat

(Bender et al. 2006, Kraytsberg et al. 200These findings are consistent with the alm

40-year-old mitochondrial theory of agin(Harman 1972), which postulates a vicious

cle whereby somatic mtDNA mutations [p

dominantly deletions (Pallotti et al. 1996)] gerate excessive reactive oxygen species (ROand these, in turn, further damage mtDN The main objection to this hypothesis ca

from clinical experience because the mution loads recorded in most postmitotic t

sues during normal aging are at least oorder of magnitude lower than those fou

106 DiMauro Schon


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Table 4 Diseases associated with defects in mitochondrial dynamicsa

Disease Gene Protein

Dominant optic atrophy (DOA) OPA1 Dynamin-related GTPase

CMT type 2A MFN2 Mitofusin 2

CMT type 4A GDAP1 Ganglioside-induced differentiation protein 1

CMT type 6 MFN2 Mitofusin 2

AD-HDP type 3A SPG3A Atlastin (associated with spastin)

AD-HSP type 4 SPAST Spastin (microtubule severing protein)

AR-HSP type 7 SPG7 Paraplegin (AAA protease)

AD-HSP type 10 KIF5A Kinesin heavy chain

AR-HSP type 20 SPG20 Spartin (microtubule-interacting protein?)

AD-HSP type 31 REEP1 Receptor expression-enhancing protein

Infantile microcephaly DNM1L Dynamin-related protein DLP1

Huntington disease HD Huntingtin (binds HAP1)

Lissencephaly (Miller-Dieker) YWHAE 14-3-3 protein

aGenes encoding mitochondrially targeted proteins are in bold.

in patients with primary pathogenic mtDNAdeletions (e.g., KSS; Table 2). However, theproportion of-mtDNA measured in single

neurons of the substantia nigra from aged nor-mal individuals approaches or surpasses the es-timated pathogenic threshold (Bender et al.

2006, Kraytsberg et al. 2006), although neu-rons from patients with Parkinson disease do

not contain significantly more-mtDNAs thandid age-matched controls (Bender et al. 2006).

The observation that many of these neurons are

functionally impaired (COX-negative) makesconceivable the second step in the vicious cy-cle: excessive ROS generation. Although the

mitochondrial theory of aging in and by it-self does not explain either natural aging or

late-onset neurodegenerative diseases, it almostcertainly plays a role in both conditions, to-

gether with nuclear genetic factors. A dra-matic example of the importance (but not nec-essarily the functional significance) of nuclear

factors is the precocious, in fact precipitous,

aging of transgenic mice that express aproofreading-deficient POLG (Khrapko et al.2006, Kujoth et al. 2005, Trifunovic et al.

2004).The role of nuclear-encoded mitochondrial

factors in neurodegenerative disorders can beapproached by considering first the general re-

YOU CAN PAY ME NOW OR YOU CAN PAYME LATER

The classic mitochondrial diseases known as the mitochondrialencephalomyopathies are caused by mutations in the mitochon-

drial or nuclear genome that affect the respiratory chain directly.Overall, these disorders cause acute (e.g., seizures, strokes) or

subacute (e.g., ataxia, neuropathy) clinical problems that mani-fest early in life, in children or in young adults. However, as a

general rule, genetic defects in mitochondrial functions that do

notdirectly impactthe respiratory chainsuch as proteinimport,organellar dynamics, and programmed cell deathcause chronicclinical problems of much later onset, highly reminiscent of the

three more common age-related and apparently sporadic neu-rodegenerative disorders, Parkinson disease, Alzheimer disease,and amyotrophic lateral sclerosis. In fact, now that we have begun

to appreciate that the familial forms of the Big Three involve mi-tochondrial function in the guise of altered organellar dynamics,

it is no stretch of the imagination to envision the same kinds ofmitochondrial involvement even in the far-more-common spo-

radic presentations of these devastating disorders.

lationship of mitochondrial biology to neu-

rodegeneration and then the specific diseasesattributed to mutations in nuclear-encoded

proteins, most of them targeted to the mito-chondria (Tieu & Przedborski 2006).



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FRDA: Friedreichataxia

Mitochondria and Neurodegeneration

Cell death in neurodegenerative diseases usu-

ally occurs by apoptosis, more commonly bythe intrinsic mitochondrial pathway than by

the extrinsic cell-signaling pathway. The in-trinsic pathway controls activation of caspase

9, through the adaptor molecule Apaf-1, by

regulating the release of cytochrome c fromthe IMS to the cytosol. Proapoptotic and an-tiapoptotic members of the Bcl-2 family, and

also stress and survival signals, regulate therelease of cytochrome c from the ISS into

the cytoplasm. Proapoptotic signals can alsorelease proteins such as Smac/DIABLO and

Omi/HTRA2, which block IAP (inhibitor ofapoptosis) proteins to activate cell death cas-

pases. However, in the intrinsic pathway ofapoptosis, mitochondria are not merely passive

containers capable of leaking cytochrome c:Rather, their life-supporting functions areclearly linkedto their death-promoting activity.

These modulating factors include the respira-tory chain activity, with the unavoidably associ-

ated generation of ROS; mitochondrial fusionand fission; calcium homeostasis; the lipid com-

position of the mitochondrial membranes; andthe mitochondrial permeability transition.

As an obvious example of the respiratorychain influence, cytochrome c is a vital water-

soluble electron carrier, not just an executionerin apoptosis.

Also, ROS are normal byproducts of the res-piratory chain activity, and their concentrationis controlled by mitochondrial antioxidant en-

zymes, such as manganese superoxide dismu-tase (SOD2) and glutathione peroxidase. Ex-

cessive ROS production (oxidative stress) isconsidered a central feature in the pathogen-

esis of all neurodegenerative disorders (Beal2005), which explains the popularity of ROS-

scavenging compounds, such as CoQ10 or anal-ogous molecules, in therapeutic trials (Di-

Mauro et al. 2006c, Shults & Schapira 2001).A pathogenic role for ROS in age-related neu-

rodegeneration is also suggested by the cor-relation between rates of formation of mito-

chondrial reactive oxygen and nitrogen species

(RONS), rates of neurodegeneration in br

and retina, and maximum lifespan potentialsfive different mammalian species (Wright et

2004).The observation that during apoptosis

normally tubular mitochondrial network bcomes fragmented, and that the proapopto

molecule Bax colocalizes with the fusiorelated proteins DRP1 and MFN2 (Newme& Ferguson-Miller 2003), suggests a regulato

role for mitochondrial fission and fusion. mentioned above, cardiolipin has many fun

tions beyond being a scaffold for the respitory chain: One such function may be to fav

apoptosis through Bax-mediated permeabilition of the OMM. Although cardiolipin is p

dominantly a component of the IMM, it mbe present in the OMM at sites of contact w

the IMM, where Bid and Bcl-2 also clus(Newmeyer & Ferguson-Miller 2003).

The permeability transition (PT) refersa still largely hypothetical pore composed

cyclophilin D and the ANT1 protein in tIMMand of the voltage-dependent anion ch

nel (VDAC) and the peripheral benzodiazepreceptor in the OMM. Sustained openingthe PT pore is considered an obligatory step

apoptosis.

Neurodegenerative Diseases Causedby Mutations in Nuclear-EncodedProteins Targeted to Mitochondria

Friedreich ataxia (FRDA) is an autosomal cessive disorder characterized clinically by ea

onset (before 25 years of age), progressive limand gait ataxia, peripheral neuropathy with a

flexia, pyramidal signs, hypertrophic cardiomopathy, and increased incidence of diabe

The hallmark neuropathology of FRDA is d

generation of the spinocerebellar tracts alarge sensory neurons. The mutated mitochodrial protein, frataxin, is encoded by a ge

(FXN) on chromosome 9q13, andmost patieare homozygous for a GAA trinucleotide rep

expansion in the first intron of FXN. Thare loss-of-function mutations, and resid

108 DiMauro Schon


19/35

frataxin expression level correlates with the

severity of the clinical phenotype.FRDA pathogenesis is controversial because

frataxin is involved in the formation of non-heme iron-sulfur clusters (ISCs), heme biosyn-

thesis, and the detoxification of iron. Loss offrataxin causes impaired mitochondrial iron

storage and metabolism and defects in mito-chondrial enzymes containing ISCs, including

aconitase and complexes I, II, and III. Iron ac-cumulation increases ROS generation by theFenton reaction, causing oxidative damage and

further mitochondrial enzyme inactivation. Toworsen the situation, antioxidant defenses are

decreased in cultured cells from FRDA patients(Chantrel-Groussard et al. 2001). Although the

pathogenic role of oxidative stress in FRDAseemed bolstered by the beneficial effects of

the antioxidant idebenone, at least on the car-diopathy (Schulz et al. 2000), paradoxically, a

conditional neuronal frataxin knockout mouseshowed neither evidence of oxidative stress nor

improvement with antioxidants (Seznec et al.2005).

Hereditary spastic paraplegia (HSP) is theterm for a group of clinically similar disordersrather than a specific clinical entity. We have

already discussed two different mitochondrialcauses of autosomal dominant HSP: one a

defect in mitochondrial protein importationcaused by mutations in SPG13, encoding

the chaperonin HSP60 (HSP here stands forheat shock protein), and the other a defect of

mitochondrial behavior caused by mutations inthe kinesin KIF5A. More controversial is the

pathogenesis of an autosomal recessive formof HSP caused by mutations in a gene (SPG7)

encoding paraplegin, a protein highly homol-ogous to the AAA family of mitochondrial

proteases (Casari et al. 1998).Because AAApro-

teases have a quality control function ensuringthat unassembled respiratory chain subunits aredegraded, a mutatedparaplegin mayresult in anaccumulation of defective subunits choking

the importation machinery (similar to muta-tions in HSP60) and, ultimately, the respiratory

chain (Claypool et al. 2006). However, anotherfunction of paraplegin seems to involve process-

PD: Parkinson dise

ing MRPL32, a component of the large riboso-

mal subunit tightly bound to the IMM (Clay-pool et al. 2006, Nolden et al. 2005). Thus, a

mutated paraplegin may impair mtDNA trans-lation, in which case this form of HSP would

belong with the subgroup of intergenomiccommunication disorders discussed above.

Autosomal dominant HSP type 4 (SPG4) iscaused by mutations in spastin (gene SPAST),

a microtubule-severing protein located in thecytoplasm. Because mitochondria must be at-tached to microtubules for them to travel down

axons, disruption of this connection should af-fect mitochondrial mobility, and indeed, cells

of SPG4 patients showed an abnormal perinu-clear clustering of mitochondria, presumably a

consequence of an inability of mutated spastinto sever microtubules (McDermott et al. 2003).

Spastins binding partner is known as atlastin(Sanderson et al. 2006), and mutations in the

gene encoding this protein (SPG3A) also causeHSP (autosomal dominant HSP type 3A), again

implicating cargo traffic on microtubules (andalmost certainly mitochondria) in the patho-

genesis of the disorder. Autosomal recessive HSP type 20 (also

called Troyer syndrome) is due to mutations

in spartin (gene SPG20), an OMM protein(Lu et al. 2006). Spartin has a microtubule

interacting and trafficking (MIT) domain atits N-terminus (interestingly, its mitochondrial

targeting signal is located at the C-terminus),implying yet again the role of mitochondrial

trafficking in thepathogenesisof this syndromicgroup (Lu et al. 2006).

Finally, autosomal dominant HSP type 31(SPG31) is caused by mutations in recep-

tor expression-enhancing protein 1 (REEP1),a mitochondrial protein of unknown function

(Zuchner et al. 2006b).

Parkinson disease (PD) is a predominantlysporadic late-onset disorder, and the mito-chondrial theory of aging, with its nonfamilial,age-related accumulation of somatic mtDNA

deletions in the substantia nigra (coupled withbiochemical evidence of complex I deficiency),

provided an attractive pathogenic explanation.Although, as discussed above, this mechanism



20/35

HD: Huntingtondisease

per se is not sufficient to explain sporadic PD,

PD (or parkinsonism, if the diagnostic criteriaof the London Brain Bank areapplied strictly) is

familial more often than thought until five yearsago (Hardy et al. 2006). To date, six nuclear

genes have been implicated: PARK2 (disease lo-cus PARK2), encoding parkin; PINK1 (locus

PARK6), encoding PTEN-induced putative ki-nase 1, or PINK1; PARK7 (locus PARK7), en-

coding DJ-1 (Hardy et al. 2006); SNCA (locusPARK1/4), encoding -synuclein; LRRK2 (lo-cus PARK8), encoding dardarin; and HTRA2

(locus PARK13) encoding Omi/HTRA2. Allthese proteins interact directly or indirectly

with mitochondriaandseemto affect apoptosis.Mutations in PARK2 have been associated

with autosomal recessive PD. Parkin is a ubiq-uitin E3 ligase associatedwith theOMM, where

it has a protective role against mitochondrialswelling caused by ceramide-induced apopto-

sis (Darios et al. 2003). As further evidence of amitochondrial role for parkin, patients with PD

and parkin mutations have decreased complexI in leukocytes (Muftuoglu et al. 2003).

PINK1 is a mitochondrial kinase (Silvestriet al. 2005) whose precise function is unknown,but which, when mutated, causes early-onset

recessive PD and, when overexpressed, protectsagainst neuronal apoptosis (Petit et al. 2005).

Omi/HTRA2 is a serine protease localizedto the mitochondrial IMS and released into the

cytosol upon apoptosis induction. Strauss et al.(2005) found a mutation inHTRA2 in four spo-

radic patients with PD, and a polymorphismin the same gene seems to predispose to PD

development.Although mutations in DJ-1 were thought

to abolish the oxidation-induced localization ofthe protein to mitochondria (Canet-Aviles et al.

2004), good evidence demonstrates that both

wild-type and mutant DJ-1 proteins are presentin mitochondria (matrix and IMS) (Zhang et al.2005a), where they likely have an antiapoptoticfunction.

-synuclein is a cytosolic protein, but itsfunctional relationshipwith mitochondria is re-

vealed by several observations: (a) Overexpres-sion of mutant -synuclein in cell cultures im-

pairs the respiratory chain and induces oxid

tive damage; (b) transgenic mice overexpress-synuclein in neurons are overly sensitive

MPTP; (c)-synuclein-deficient mice are mresistant to respiratory chain inhibitors; a

(d) transgenic mice expressing mutantsynuclein show neuronal degeneration, acc

mulation of intraneural inclusions, and coplex IV deficiencyin thespinalcord. In humamutations in the SNCA gene cause autosom

dominant PD (Polymeropoulos et al. 1997).Autosomal recessive parkinsonism is not u

common in patients with PEO and mutatioin POLG, and it can be seen even in young p

tients without PEO (Davidzon et al. 2006).Huntington disease (HD), an auto

mal dominant disorder, penetrates fully mid-adult life and is characterized by choreo

thetotic movements, emotional problems, adementia. Selective degeneration of stria

neurons and marked atrophy of caudate aputamen occur. HD is caused by abnormexpansion of a CAG repeat in the HD gene

chromosome 4, which encodes a protein calhuntingtin (HTT). Although HTT is not a m

tochondrial protein, four pathogenic scenarall involve mitochondrial dysfunction.

The first scenario postulates an enemetabolismdefectandisbasedonmagneticr

onance spectroscopy (MRS) of the brain (shoing lactate peaks in the occipital cortex a

basal ganglia) andof muscle(showing decreasPCr/Pi ratios). Both direct and indirect b

chemical evidence also show impaired enerproduction because the activities of respirato

chain complexes II and III were decreasedpostmortem HD brains, and inhibition of co

plex II by malonate in experimental animcaused pathological lesions resembling thosehuman HD.

The second scenario is based on evidenthat polyglutamine accumulation impairs c

cium handling, causing calcium-induced pmeability transition and cytochrome c rele

(Choo et al. 2004).The third pathogenic mechanism in a sen

includes the previous two andsuggests that mtant HTT impairs mitochondrial function

110 DiMauro Schon


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a more general way, by repressing PGC-1-

regulated gene transcription of many nucleus-encoded mitochondrial genes; PGC-1 (perox-

isome proliferators-activated receptor- coac-tivator 1) is a master transcriptional coactiva-

tor that controls mitochondrial biogenesis andoxidative phosphorylation (Greenamyre 2007).

Fourth, and perhaps most provocative, aphysical interaction that impacts organellar

mobility in this disease may exist between HTTand mitochondria. HTT binds to huntingtin-interacting protein 1 (HAP1). HAP1 is a cy-

tosolic protein that associates with micro-tubules and other membranous compartments

of the cell, including mitochondria (Gutekunstet al. 1998). However, using immuno-electron

microscopy, HAP1 was localized to smallpuncta in both the nucleus and the mitochon-

dria (Gutekunst et al. 1998). In addition, HAP1interacts with the p150Glued subunit of dyn-

actin (DYNC1LI2) (Engelender et al. 1997, Liet al. 1998). The relationship between HTT,

HAP1, and dynactin may explain the observa-tion that microtubules are destabilized in HD

(Trushina et al.2003)and that mutantHTT im-pairs axonal trafficking in mammalian neurons(Trushina et al. 2004).

Amyotrophic lateral sclerosis (ALS) is alate-onset, sporadic disorder typically affecting

both lower (anterior horn cells of the spinalcord) and upper (cortical) motor neurons, caus-

ing widespread paralysis and premature death.About 5%10% of patients have a familial form

of ALS (FALS), and 20% of these harbormutations in the Cu,Zn-superoxide dismutase

1 (SOD1) gene. SOD1 is present in both thecytosol and in the IMS (Sturtz et al. 2001).

Transgenic mouse models overexpressing mu-tant SOD1 also develop motor neuron degen-

eration. Most pathogenic mutations do not im-

pair SOD1 activity, and investigators assumethat they cause a toxic gain of function.Mitochondrial involvement in FALS is sug-

gested by the early mitochondrial degenera-

tion observed in motor neurons from patientsand transgenic animals, by the presence of mu-

tant SOD1 and of aggregates containing mu-tant SOD1 in the mitochondrial matrix and

ALS: amyotrophiclateral sclerosis

FALS: Familial ALS

AD: Alzheimerdisease

FAD: familial AD

IMS (Liu et al. 2004), and by the impaired mito-

chondrial functions (respiratory chain and cal-cium homeostasis) seen in transgenic mice.

Studies also report respiratory chain abnor-malities in spinal cord of sporadic ALS pa-

tients (Borthwick et al. 1999, Wiedemann et al.2002). Conversely, one patient with primary

mitochondrial disease (a microdeletion in theCOX I gene of mtDNA) had a typical, albeit

early-onset, ALS phenotype (Comi et al. 1998).Alzheimer disease (AD) is a neurodegener-

ative dementing disorder of late onset, with a

relatively long course (Mattson 2004). Stud-ies show progressive neuronal loss, especially

in the cortex and the hippocampus. The twomain histopathological hallmarks of AD are the

accumulation of extracellular neuritic plaques,consisting mainly of -amyloid (A), and of

neurofibrillary tangles, consisting mainly of hy-perphosphorylated forms of the microtubule-

associated protein tau (Goedert & Spillantini2006, Roberson et al. 2007). Most AD cases are

sporadic, but three genes have been identifiedin the familial form (FAD): amyloid precursor

protein (APP), presenilin 1 (PS1; gene PSEN1),and presenilin 2 (PS2; gene PSEN2). Vari-ants in two genes predispose people to SAD:

apolipoprotein E isoform 4 (APOE4) (Corderet al. 1993) and SORL1, a neuronal sorting re-

ceptor (Rogaeva et al. 2007).Abundant evidence indicates that mitochon-

dria are affected in AD, including reductionin brain energy metabolism shown by positron

emission tomography (Azari et al. 1993),mitochondrial metabolic enzyme deficiency

(Mastrogiacomo et al. 1993, Sheu et al. 1985),and respiratory chain deficiency (Bonilla et al.

1999, Kish et al. 1992), etc. However, a directrole for mitochondria in AD pathogenesis has

been controversial, hinging mainly on findings

related to both APP and PS1. The current view is that APP is locatedpredominantly in the plasma membrane, whereit is cleaved in a series of proteolytic events

(e.g., by -, -, and -secretases) to releaseintra- and extracellular fragments of uncertain

function. However, Avadhanis group showedby genetic dissection and expression of APP



22/35

constructs in vitro that the APP protein con-

tains a possible mitochondrial targeting signalat its N-terminus (Anandatheerthavarada et al.

2003). They then showed that nonglycosylatedfull-length and C-terminal truncated APP

accumulates exclusively in the mitochondrialproteinimport channels in AD brains but not in

age-matched controls (Devi et al. 2006). Thisresult was consistent with (a) the identification

of A42 in mitochondria (Lustbader et al.2004, Manczak et al. 2006); (b) the observationthat A binds to 17--hydroxysteroid dehy-

drogenase, type 10 (HADH2), a mitochondrialmatrixprotein involved in fatty acid metabolism

(Lustbader et al. 2004); and (c) the finding that-amyloid inhibits respiratory chain function

in isolated rat brain mitochondria (Casley et al.2002). However, it is unclear how A could

be derived from its precursor APP withinmitochondria, given that the putative requi-

site initial processing proteases (e.g., - and-secretases) have not been found in mitochon-

dria. A could be imported into mitochondria,but at present there is no coherent explanation

as to how this might be accomplished.Researchers disagree with regard to PS1.

Using immunohistochemical techniques, PS1

has been localized to numerous membranouscompartments in cells. These include the endo-

plasmic reticulum (ER) (Walter et al. 1996), theGolgi apparatus (Annaert et al. 1999, Siman &

Velji 2003), endosomes/lysosomes (Runz et al.2002, Vetrivel et al. 2004), the nuclear enve-

lope (Honda et al. 2000), and the plasma mem-brane (Schwarzman et al. 1999), where they

are especially enriched at intercellular contactsknown as adherens junctions (Marambaud et al.

2002). PS1 hasnot been found in mitochondria,except by one group that used Western blot-

ting and immunoelectron microscopy, not im-

munohistochemistry, to localize PS1 to the ratmitochondrial inner membrane (Ankarcrona &Hultenby 2002, Hansson et al. 2004).

Besides PS1, the -secretase complex con-

tains at least three other proteins: APH1,PEN2, andnicastrin(De Strooper 2003). Using

immunoelectron microscopyandWesternblot-ting, all three proteins have been localized to rat

mitochondria (Hansson et al. 2004). Howev

localization of-secretase subunits, includiPS1, to mitochondria has not been confirm

or demonstrated by other, more definitimethods.

Given that mitochondria play a role in tpathogenesis of several neurodegenerative d

eases (Figure 8), it would not be unreasonato invoke similar mechanisms for AD, and pecially a mechanism involving mitochondr

movement and localization (Kins et al. 200This possibility is supported by two obser

tions.First,aPS1mutation(M146V)inamouPS1 knock-in model impairs axonal transp

and also increases tau phosphorylation (Pigiet al. 2003). Second, axonal defects, consisti

of swellings that accumulate abnormal amouof microtubule-associated and molecular m

tor proteins, organelles, and vesicles, have befound in both sporadic AD patients and

transgenic mouse models of FAD (Stokin et2005).

MITOCHONDRIAL PSYCHIATRY

Given the brains high dependence on oxidat

metabolism, it is hardly surprising that primmitochondrial disorders often cause cognitdeficits: dementia in adults and mental retard

tion or neuropsychological regression in chdren. Researchers have paid comparatively l

attention to the relationship between psycatric diseases and mitochondrial dysfunctio

For the sake of order, let us consider separatthe psychiatric manifestations of primary m

tochondrial diseases and the evidence of michondrial dysfunction in patients with isola

primary psychiatric illnesses.Although the literature is replete with an

dotal reports of psychiatric problems, mos

severe depression, in patients with mtDNrelated diseases (DiMauro et al. 2006b), thhave been few systematic neuropsychiat

studies of large cohorts of patients with knowmitochondrial diseases. We have reported pliminary data on a large group of MELAS a

MERRF families (102 persons from 30 kdreds), including notonly patients but also th

112 DiMauro Schon


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oligosymptomatic or asymptomatic maternal

relatives. In MELAS families (harboring theA3243G mutation), 42% of fully symptomatic

carriers reported depressive symptoms, but22% of asymptomatic and 29% of oligosymp-

tomatic carriers also had depressive traits, com-pared with only 7% of the control group

(Kaufmann et al. 2002). In MERRF familieswith the A8344G mutation, 80% of fully symp-

tomatic patients, 20% of oligosymptomaticcar-riers, and none of the asymptomatic carriers re-ported depressive symptoms. The finding that

even asymptomatic carriers of the MELAS mu-tation were prone to depression suggested that

psychiatric problems might be an early clinicalexpression of the mutation, which is also sup-

ported by correlative neuropsychological and MRS studies, showing cerebral lactic acido-

sis in asymptomatic MELAS relatives and acorrelation between neuropsychological scores

and ventricular lactate levels (Kaufmann et al.2004).

Among the Mendelian mitochondrial dis-eases, depression is frequent in patients with

defects of intergenomic communication, PEO,and multiple mtDNA deletions. Psychiatricproblems are especially common in patients

harboring mutations in ANT1, PEO1, andPOLG (DiMauro et al. 2006b).

Although maternal inheritance of bipolardisorder had been suggested by a higher-than-

expected frequency of affected mothers and in-creased risk of illness in maternal relatives, mu-

tations in mtDNA have been excluded as causesof the disease (Kirk et al. 1999). However, mi-

tochondrial dysfunction may still be involvedin bipolar disorder pathogenesis through sev-

eral pathogenic mechanisms, many of which,not surprisingly, are similar to those proposed

for neurodegenerative diseases. These include

alterations of calcium homeostasis (Kato et al.2002), downregulation of genes controlling mi-tochondrial energy metabolism (Konradi et al.2004), and impaired mtDNA replication (Kaki-

uchi et al. 2005), all possibly related to a change(-116C>G) in the promoter region ofXBP1, a

pivotal gene in theendoplasmic reticulum stressresponse (Kakiuchi et al. 2003).

Another gene that has been highlighted

in the pathogenesis of both bipolar disorderand schizophrenia is Disrupted in schizophre-nia 1 (DISC1), so called because a disrup-tion of this gene by the chromosome 1 break-

point of a balanced t(1;11) translocation did,in fact, cosegregate with schizophrenia and re-

lated mood disorders in a large Scottish family(St Clair et al. 1990). The association of DISC1and schizophrenia was confirmed in Finnish,

American,Japanese, andTaiwanese populations(Roberts 2007) and extended to bipolar dis-

order (Maeda et al. 2006). Although its pre-cise role remains unclear, DISC1 bound pre-

dominantly to mitochondria (James et al. 2004)and interacted with several proteins, including

FEZ1, LIS1, and NUDEL, which are also in-volved, at least indirectly, in neurodegenerative

diseases (Figure 8). Overexpression of DISC1in COS-7 cells disrupts mitochondrial orga-

nization and leads to the formation of ring-like structures, suggesting a role of this proteinin controlling mitochondrial dynamics (Millar

et al. 2005). The distribution of DISC1 in thedeveloping and adult brain (frontal cortex, hip-

pocampus, thalamus) and its involvement withneuronal migration, neurite outgrowth, and

synaptic plasticity support the pathogenic roleof genetic variants in psychiatric disorders.

CONCLUSIONS

Two main concepts emerge from this overview

of mitochondrial disorders in the nervous sys-tem. The first is a sense of amazement that this

small organelle, a foreign guest that took uppermanent residence in all our cells, partici-

pates in such a wide array of neurological dis-orders, from LS in infancy to AD in old age. A

second, and related, consideration is that there

is much more to mitochondria than the stan-dard textbook gloss that they are the power-houses of the cell that only produce ATP. Be-

sides ATP production, mitochondria performvaried functions that are important for cell lifeand death, including ROS generation, calcium

homeostasis, and programmed cell death, andthe pathogenesis of any mitochondrial disease



24/35

is likely to involve, at least to some extent and

at some point, all these functions. In fact, wehave seen that even primary defects of the res-

piratory chainthe most likely causes of powerfailuresare so diverse as to defy a unitary

mode of pathogenesis that invokes merely theloss of ATP capacity.

In the nervous system, mitochondrial dy-namics are crucial to guarantee long distance

delivery and balanced distribution of energy

(in addition to all the other functions) to t

farthest reaches of neurons (synapses and dedrites). Although the concept and the rules

mitochondrial dynamics have been latecomto the field of mitochondrial diseases, alt

ations in the topology and topography of tmost plastic of organelles may well be the u

fying theme providing, more often than nocommon finalpathogenic pathway for neurodgenerative and psychiatric diseases alike.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of t

review.

ACKNOWLEDGMENTS

This work has been supported by grants from the National Institutes of Health (NS 11766 aHD32062), from the Muscular Dystrophy Association, and from the Marriott Mitochondr

Disorder Clinical Research Fund (MMDCRF). The authors are grateful to Drs. Michio Hiraand Lewis P. Rowland for revising the manuscript and to Drs. Eduardo Bonilla and Kurenai Ta

for providing Figures 3 and 4.

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