Funciones y Disfunciones de La Dinamica Mitocondrial 2007

8/3/2019 Funciones y Disfunciones de La Dinamica Mitocondrial 2007

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I the 1950s, semia eectr micrscpy stdies edt the caica iew f mitchdria as bea-shapedrgaees. These stdies reeaed the trastrctrahamarks f mitchdria, which icde dbe ipidmembraes ad sa ier membrae fds termedcrita. Recet stdies hae ed t reewed appre-ciati fr the fact that the mitchdria strctreis highydyamic1,2. Mitchdria hae drasticaydifferet mrphgies depedig the ce typead, ee i the same ce, mitchdria ca take a rage f mrphgies, frm sma spheres rshrt rds t g tbes. I fibrbasts, fr exampe,mitchdria isaized with frescet prteis rspecific dyes typicay frm tbes with diameters f~0.5 mm, bt their egths ca rage frm 110 mmr mre.

Ee mre remarkaby, imagig stdies i ieces idicate that mitchdria cstaty me adderg strctra trasitis. Mitchdria tbesme with their g axes aiged ag cytskeetatracks3. Idiida mitchdria ca ecter eachther drig these memets ad derg fsi,

restig i the mergig f the dbe membraes adthe mixig f bth ipid membraes ad itramit-chdria ctet (BOX 1). Cersey, a idiidamitchdri ca diide by fissi t yied tw rmre shrter mitchdria.

What are the mecar mechaisms that deriethese sa behairs, ad d they hae cse-qeces fr mitchdria fcti ad ce physi-gy? I this Reiew, we discss the dyamic atref mitchdria ad smmarize the mechaisms thatdrie mitchdria fsi ad fissi. I additi, wediscss recet isights it hw these prcesses affectthe fcti f mitchdria. As we as ctrig the

shape f mitchdria, fsi ad fissi are crciafr maitaiig the fctia prperties f the mit-chdria ppati, icdig its respiratry capacity.Mreer, mitchdria dyamics has key res imammaia deepmet, seera erdegeeratiediseases ad apptsis.

Mitochondria as dynamic organelles

By seera criteria, mitchdria are dyamicrgaees. First, the shape ad size f mitchdriaare highy ariabe ad are ctred by fsi adfissi. Secd, mitchdria are actiey trasprtedi ces ad they ca hae defiedsbcear distrib-tis. Fiay, the itera strctre f mitchdriaca chage i respse t their physigica state.

Dynamic shape. The egth, shape, size ad mberf mitchdria are ctred by fsi ad fissi(FIG. 1a). At steady state, the freqecies f fsi adfissi eets are baaced4 t maitai the eramrphgy f the mitchdria ppati. Whethis baace is experimetay pertrbed, dramatic

trasitis i mitchdria shape ca ccr. Geeticstdies i yeast ad mammas idicate that ces witha high fsi-t-fissi rati hae few mitchdria,ad that these mitchdria are g ad highy iter-cected58 (FIG. 2). Cersey, ces with a w fsi-t-fissi rati hae mers mitchdria that aresma spheres r shrt rds these are fte referredt as fragmeted mitchdria. In vivo, sch chagesi dyamics ctr mitchdria mrphgy dr-ig deepmet. Fr exampe, drig Drosophilamelanogaster spermatgeesis, may mitchdriasychrsy fse t frm the Nbnkrn tructur,which is reqired fr sperm mtiity9.

Division of Biology,

California Institute of

Technology, Pasadena,

California 91125, USA.

Correspondence to D.C.C.

e-mail: [email protected]

doi:10.1038/nrm2275

Publihd onlin

10 Octobr 2007

Cristae

Invagination of th

mitochondrial innr

mmbran.

Nebenkern structure

A cytoolic tructur, found in

om inct prmatid, that i

formd by th fuion of

mitochondria.

Functions and dysfunctions ofmitochondrial dynamicsScott A. Detmer and David C. Chan

Abstract | Recent findings have sparked renewed appreciation for the remarkably dynamic

nature of mitochondria. These organelles constantly fuse and divide, and are actively

transported to specific subcellular locations. These dynamic processes are essential for

mammalian development, and defects lead to neurodegenerative disease. But what are the

molecular mechanisms that control mitochondrial dynamics, and why are they important formitochondrial function? We review these issues and explore how defects in mitochondrial

dynamics might cause neuronal disease.

R E V I E W S

870 | novEMBER 2007 | voluME 8 www../w/
mailto:[email protected]:[email protected]


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Wild type+

Fusion mutant

+

Anterograde

Th dirction from th cll

body toward th priphry.

Retrograde

Th dirction from priphral

rgion toward th cll body.

Oxidative phosphorylation

A biochmical pathway for ATP

production that rult in

oxygn conumption and i

localizd to th mitochondrial

crita.

Dynamic subcellular distribution. Mitchdria tras-prt is reqired t distribte mitchdria thrghtthe ce (FIG. 1b). I mst ces, mitchdria are highymtie ad trae ag cytskeeta tracks. Mitchdriatrasprt depeds the acti cytskeet i bddigyeast10 ad bth acti ad micrtbes i mam-maia ces3,11,12. Depedig the cear ctext,these trasprt prcesses ca esre prper iheritacef mitchdria r ca recrit mitchdria t actie

regis f the ce. Fr exampe, i bddig yeast,mitchdria are trasprted it ad retaied i thedeepig bd t esre mitchdria iheritace tthe daghter ce10.

This regati f mitchdria distribti is par-ticary eidet i ers. Qatitatie measremetsf era mitchdria trasprt hae reprted ratesragig frm 0.4 mm mi1 (ReF. 13) t 0.11 mm sec1

(ReFs 11,14,15). Sch directed memets are t cti-s; rather, they are satatry, with pases fte fwedby a reersa f directi. These patters might refectthe attachmet ad detachmet f cytskeeta mtrs.Athgh these memets ca appear chatic, seera

ies f eidece frm era stdies sggest that mit-chdria trasprt is regated. First, mitchdria arerecrited t regis with high eergy demads, icdigactie grwth ces, presyaptic sites ad pstsyapticsites13,16,17. Sch recritmet is regated by era acti-

ati, frther argig that the recritmet f mitch-dria is respsie t the ca metabic state. Secd,era mitchdria pase mst fte at sites that ackther mitchdria, restig i a we-spaced axamitchdria distribti14. Third, stdies with themembrae-ptetia idicatr dye JC-1 sggest that mit-chdria with high membrae ptetia preferetiaymigrate i the antrograd directi, whereas mitch-dria with w membrae ptetia me i the rtrograddirecti14. These migrati patters sggest that actiemitchdria are recrited t dista regis with higheergy reqiremets, whereas impaired mitchdriaare retred t the ce sma, perhaps fr destrctir repair. Fiay, mitchdria trasprt ag axsrespds t ca ccetratis f ere grwth factr(nGF), sggestig that specific sigaig pathways

ctr mitchdria recritmet ad reteti16,18.

Dynamic internal structure. I additi t chages ithe era shape f mitchdria, the itera strctresf mitchdria are as dyamic. Three-dimesiatmgraphy f crypresered sampes has prided ew

iews f ier membrae rgaizati ad pasticity19.The ier membrae ca be diided it distict regis:the ier bdary membrae, the cristae membraead the cristae jctis (FIG. 1c). The ier bdarymembrae cmprises the regis i which the iermembrae is i cse prximity t the ter membrae.These regis are prbaby imprtat fr prtei imprtad might be the sites f cped ter ad ier mem-brae fsi. The cristae jctis are arrw eckregis that separate the ier bdary membraefrm the ited cristae membrae. Cytchrme c, aitermembrae-space prtei, is eriched i the spacethat is ecased by cristae membraes, ad the regatedpeig f cristae jctis might be imprtat fr itsrecaizati drig apptsis20.

These regis f the mitchdria ier membraeare t y mrphgicay distict bt as appear tcstitte separate fctia dmais. Prteis thatare ied i the trascati f prteis thrghthe ier membrae, sch as the TIM23 cmpex, areeriched i the ier bdary membrae, whereas

prteis that are ied i oxidativ phophorylationare eriched i the cristae membraes2123. I additi,the strctre f mitchdria membraes is iked t themetabic state f mitchdria (FIG. 1c). Prified mit-chdria paced i w ADP cditis hae imitedrespirati ad hae a rthdx mrphgy, charac-terized by arrw cristae ad few cristae jctis percristae cmpartmet. uder high ADP ad sbstratecditis, isated mitchdria hae high respiratryactiity ad a cdesed mrphgy, characterizedby arger cristae ad seera cristae jctis per cristaecmpartmet19. It is kw hw ier membraescert betwee these states, bt ier membrae fsi

Box 1 | What happens to mitochondrial components after fusion?

In time-lapse movies of labelled mitochondria in living cells, mitochondria are observed

to undergo cycles of fusion and fission. With each fusion event, two mitochondria are

merged into one. Intuitively, true fusion would be expected to involve outer membrane

and inner membrane fusion, which would also result in mixing of the matrix contents.

Indeed, these expectations have been experimentally confirmed. Apparent fusion events

that have been visualized in cells can be confirmed by a cell-hybrid mitochondrial fusion

assay6,32 (see figure). In this assay, mitochondria in two distinct cell lines are differentially

labelled with mitochondrially targeted green fluorescent protein (GFP) and DsRed.The cell lines are co-plated onto cover slips and exposed briefly to polyethylene glycol,

a chemical that induces adjacent cells to fuse into cell hybrids. After a recovery period,

the cell hybrids are examined for mitochondrial fusion. In cell hybrids from normal cells,

mitochondrial fusion results in mitochondria that carry both GFP and DsRed (see figure,

top). Cells that are defective for mitochondrial fusion form cell hybrids with distinct red

and green mitochondria (see figure, bottom). A conceptually similar assay can be

performed with yeast cells by allowing labelled yeast strains to mate and form zygotes4.

By using matrix-targeted fluorophores, these assays show that mitochondrial fusion

results in mixing of the matrix contents. Moreover, by using mitochondrial markers that

are localized to the outer or inner membranes, fusion of the individual membranes can

be experimentally demonstrated; under normal conditions, outer and inner membrane

fusion appear to be closely synchronized.

An important question is what happens to mitochondrial DNA (mtDNA) after fusion.

Each mitochondrion contains multiple copies of the mtDNA genome that are organized

into one or more nucleoids. After fusion, these nucleoids appear to be motile and canpotentially interact with each other73. In mammalian cells, mtDNA recombination has

been documented, but its extent and importance is unclear.

R E V I E W S

nATuRE REvIEWS |molecular cell biology voluME 8 | novEMBER 2007 |871
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4803&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10431&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10431&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4803&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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Nucleus

Fusion

Fission

+

Anterogrademovement

Retrogrademovement

IMS OM

IMIBM

CM

CJ

a

b

c

Low [ADP]

High [ADP]

Condensed morphology Orthodox morphology

Coiled coil

A tructural motif that i

formd by polypptid

qunc that contain

hydrophobic hptad rpat.

Dynamin

A larg GTPa that i thought

to mdiat vicl ciion

during ndocytoi.

ad fissi might be ied19. Take tgether, thesebseratis idicate that ier membrae mrphgyis itimatey reated t bieergetics, athgh the casareatiship remais cear.

Mediators of fusion and fission

Mecar aaysis f mitchdria mrphgy begawith the discery i 1997 f the D. melanogasterfsifactr fzzy is (FZo), a mitchdria ter mem-brae GTPase that is reqired fr the fsi f mit-chdria drig spermatgeesis9. FZo is the fdig

member f the mitfsi famiy f GTPases. The yeastrthge,Fz1, has a csered re i mitchdriafsi24, ad geetic screes i yeast hae idetifiedadditia mdatrs f mitchdria fsi adfissi2,25 (FIG. 3b). The cre machieries that mediatemitchdria fsi ad fissi are best derstdi yeast. Seera f these cmpets hae fctiaycsered mammaia hmges. Mre cmpre-hesie discssis f the mecar mechaisms fmitchdria fsi ad fissi hae bee presetedi recet reiews (fr exampe, see ReF. 1).

Mitochondrial fusion. I yeast, the cre mitchdriafsi machiery csists f tw GTPases: Fz1 adMgm1(FIG. 3). Fz1 is cated the mitchdria termembrae ad is essetia fr fsi f the ter mem-braes24,26. The mammaia hmges f Fz1 are themitfsisMFn1 adMFn2. These tw reated prteisfrm hm-igmeric ad heter-igmeric cmpexesthat are essetia fr fsi6,27,28. Mitfsis are reqired adjacet mitchdria drig the fsi prcess,

impyig that they frm cmpexes i trans betweeappsig mitchdria26,29. A heptad repeat regi fMFn1 has bee shw t frm a atiparae coildcoil that is prbaby ied i tetherig mitchdriadrig fsi29.

Mgm1 is a dynamin-reated prtei that is essetiafr fsi f the mitchdria ier membraes iyeast30, a fcti that is csistet with its caizatit the itermembrae space ad its assciati with theier membrae. The mammaia rthge oPA1is as essetia fr mitchdria fsi28,31. I yeast,the ter membrae prteiug1 physicay iks Fz1ad Mgm1, bt mammaia rthge has yet beediscered2.

The mmbran potntial acrss the mitchdriaier membrae is maitaied by the eectr tras-prt chai ad is essetia fr mitchdria fsi26,32.Iphres that dissipate the mitchdria membraeptetia case mitchdria fragmetati, wig ta ihibiti f mitchdria fsi32,33. I a in vitrofsi assay, bth the prt ad the eectrica gradietcmpets f the membrae ptetia are imprtat26.The mechaistic ik betwee membrae ptetia adfsi remais t be resed, bt e factr appears tbe the depedece f pst-trasatia prcessig foPA1 the membrae ptetia34.

Recet wrk has as idetified mitchdria ipids

as imprtat factrs i fsi. Mitchdria mrph-gy screes i yeast idetified members f the rgotrolsythesis pathway as beig reqired fr rma mit-chdria mrphgy35,36. Recety, mitchdriaphsphipase D has bee idetified as a prtei that isimprtat fr mitchdria fsi37. This mitch-dria ter membrae ezyme hydryses cardiipi tgeerate phsphatidic acid. Iterestigy, ergster hasbee assciated with yeast ace fsi38, ad phs-phatidic acid is thght t pay a part i geeratig themembrae cratre that is reqired fr sNARe-mediatedfsi39. Ths, specific ipids might hae simiar res idistict types f membrae fsi.

Figure 1 | md d . | Mitochondrial fusion and fission

control mitochondrial number and size. With fusion, two mitochondria become a single

larger mitochondrion with continuous outer and inner membranes. Conversely, a single

mitochondrion can divide into two distinct mitochondria by fission. | In mammalian

systems, mitochondria are distributed throughout the cytoplasm by active transport along

microtubules and actin filaments. Distinct molecular motors transport the mitochondria in

anterograde or retrograde directions. | Inner membrane dynamics. The diagram

indicates the different regions of the inner membrane. The bottom panels show electron

microscopy (EM) tomograms of two mitochondria under different metabolic conditions

(red, outer membrane; yellow, inner boundary membrane; green, cristae membrane).

Cristae organization can vary widely, often in response to the bioenergetic state of the

cell: an orthodox cristae morphology, with narrow cristae and few cristae junctions per

cristae compartment, is found in low ADP conditions, whereas a condensed morphology,

with larger cristae and several junctions per cristae compartment, is found in high

ADP conditions19. EM images reproduced with permission from ReF. 19 (2006) Elsevier.CJ, cristae junction; CM, cristae membrane; IBM, inner boundary membrane; IM, inner

membrane; IMS, intermembrane space; OM, outer membrane.

R E V I E W S

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No fusion Wild type No fission

Mfn-null DRP1 K38A

Mitochondrial membrane

potentialTh lctrochmical gradint

that xit acro th

mitochondrial innr

mmbran.

Ergosterol

A troid compound that i a

componnt of yat cll

mmbran and which might

hav a rol imilar to that of

choltrol in mammalian cll

mmbran.

SNARE

(olubl Nthylmalimid

nitiv fuion protin (NsF)attachmnt protin (sNAP)

rcptor). A highly hlical

protin that mdiat th

pcific fuion of vicl with

targt mmbran.

F-box protein

A protin containing an Fbox

motif, a mall domain that i

ud for protin intraction.

Th btcharactrizd Fbox

protin ar componnt of an

e3 ubiquitin liga, and hlp in

ubiquitindpndnt protin

dgradation by rcognizing

pcific ubtrat.

-barrel protein

A protin compod of a

ht that i rolld up

into a cylindr. On uch

mitochondrial barrl protin

i VDAC (voltagdpndnt

anion channl), which form a

por in th outr mmbran.

Kinesin

A microtubulbad molcular

motor protin that i mot

oftn dirctd toward th plu

nd of microtubul.

Mitochondrial fission. Mitchdria fissi reqires

the recritmet f a dyami-reated prtei (Dm1 iyeast ad DRP1 i mammas) frm the cyts (FIG. 4).Bth Dm1 ad DRP1 assembe it pctate spts mitchdria tbes, ad a sbset f these cmpexesead t prdctie fissi eets5,7,8. By aagy with thecassica fcti f dyami i edcytsis, Dm1ad DRP1 are thght t assembe it rigs ad spirasthat ecirce ad cstrict the mitchdria tbedrig fissi25. Csistet with this mde, prifiedDm1 ca ideed frm heica rigs ad spiras in vitro,with dimesis that are simiar t thse f cstrictedmitchdria40. Mreer, Dm1 assemby is reqiredfr fissi actiity41.

The recritmet f Dm1 t yeast mitchdria fis-si sites ies three ther cmpets. oe f theseis Fis1, a mitchdria itegra ter membrae prteithat is essetia fr fissi4244. Fis1 bids idirecty tDm1 thrgh e f tw mecar adaptrs, Md1r Caf4 (ReF. 45)(FIG. 4b). Either Md1 r Caf4 is sffi-ciet t aw the Fis1-depedet recritmet f Dm1,athgh Md1 has a mre imprtat re i mediatigfissi.FIS1, the mammaia hmge f Fis1, is asessetia fr mitchdria fissi46, bt hmgesf Md1 r Caf4 are crrety kw. FIS1 ad DRP1are as reqired fr the fissi f perxismes47,48.

Other regulators of dynamics

Mitchdria fsi ad fissi actiities are prbabycrdiated with cear physigy. I yeast, the steady-state ees f Fz1 are ctred by the Fbox protinMdm30, which egatiey regates Fz1 ees i aprteasme-idepedet maer49,50. I mammaiaces, pst-trasatia mdificati f DRP1 regates itsfcti i mitchdria fissi. The mitchdria E3biqiti igase MARCH5 is essetia fr mitchdriafissi51. This reqiremet is prbaby reated t the abi-ity f MARCH5 t prmte DRP1 biqityati ad tassciate physicay with biqityated DRP1 (ReFs 52,53).Frthermre, drig apptsis, smyati f DRP1 isactiated i a BAX- ad/r BAK-depedet maer54.

This mdificati f DRP1 might affect its assciatiwith mitchdria membraes. Mitchdria fissi isas regated by the ce cyce. Fr exampe, mitchdriai Hela ces are say tbar, bt they becme mrefragmeted drig mitsis, a pheme that mightfaciitate the partitiig f mitchdria t daghterces drig cytkiesis. This regated fragmetati fmitchdria is de t icreased mitchdria fissi,ad phsphryati f DRP1 drig mitsis has beeimpicated55.

I additi t the gees that ecde cre fsi adfissi cmpets, ther gees ca affect mitch-dria mrphgy. large-scae isa screes fr aberratmitchdria mrphgy i mtat yeast hae yiededmers gees f iterest ad prided geera isightsit the ctr f mitchdria mrphgy35,36. Thesescrees sggest that seera cear pathways ifecemitchdria mrphgy ad iheritace, icdigergster bisythesis, mitchdria prtei imprt,acti dyamics, esicar fsi ad biqiti-mediatedprtei degradati. The cse iterpay betwee mit-

chdria prtei imprt ad mrphgy has beeemphasized by the recet fidig that the mitchdriamrphgy geesMMM1,MDM10 adMDM12 hae adirect re i the assemby fbarrl protin i the termitchdria membrae56.

Proteins that are required for mitochondrial transport.Eergy-depedet mecar mtrs trasprt mitch-dria ag cytskeeta fiamets. Ag micrtbes,mtipe kinin famiy members ad cytpasmic dyninhae bee impicated i atergrade ad retrgrademitchdria trasprt, respectiey3. Recet wrk hascarified the ikage betwee mitchdria ad kiesi-1.Geetic screes i D. melanogasteridetified miltonadMiro, bth f which are reqired fr atergrademitchdria trasprt i ers57,58. Mit iteractsdirecty with kiesi ad Mir, which is a mitchdriater membrae prtei that has GTPase ad Ca2+-bid-ig eFhand domain59. I yeast, disrpti f the Mirrthge Gem1 rests i abrmaities i mitch-dria mrphgy ad pr respiratry actiity60. BthGTP-bidig ad Ca2+-bidig mtifs are essetia frGem1 fcti, which appears t t be ied ifsi r fissi. Depedig the ce type, mitch-dria ca as trae ag acti fiamets der the ctrf mysi mtrs3.

Proteins that mediate inner membrane morphology.Stdies f mitchdria ier membrae strctre arecmpicated by the itimate ik betwee mitchdriabieergetics ad cristae strctre. As a rest, disrptif the prteis that are imprtat fr bieergetics caead t a secdary effect ier membrae strctre.neertheess, seera prteis prbaby hae a specificre i ctrig cristae strctre. I additi t theirres i mitchdria fsi, Mgm1 ad oPA1 areimprtat fr cristae strctre. lss f Mgm1 i yeastr kckdw f oPA1 i mammaia ces rests idisrgaized ier membrae strctres30,6164. I bthcases, hm-igmeric iteractis are ied30,64.

Figure 2 | md d . Mitochondrial

length, size and connectivity are determined by the relative rates of mitochondrial fusion

and fission. In wild-type cells (shown in the central panel), mitochondria form tubules of

variable length. In the absence of mitochondrial fusion (for example, in mitofusin (Mfn)-

null cells (shown in the left panel), which lack MFN1 and MFN2), unopposed fission results

in a population of mitochondria that are all fragmented. Conversely, decreased fission

relative to fusion (for example, in DRP1 K38A cells (shown in the right panel), which have

a dominant-negative form of dynamin-related protein-1 (DRP1)) results in elongated and

highly interconnected mitochondria. Scale bar represents 10 mm.

R E V I E W S

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IMfusion

OMfusion

Fzo1

IMS

OM

IM

Cristae

s-Mgm1

I-Mgm1

Ugo1

a

b

DyneinA microtubulbad molcular

motor that i dirctd toward

th minu nd of microtubul.

EF-hand domain

A hlixloophlix protin motif

that can bind a Ca2+ ion.

Mitochondrial F1F

0ATP

synthase

A larg, multiubunit nzym

mbddd in th

mitochondrial crita that u

th proton gradint acro th

innr mmbran to ynthiz

ATP.

Mitochondrial DNA

(mtDNA). A circular gnom

(~16 kb in mammal) locatd

in th mitochondrial matrix

that ncod 13 polypptid

of th lctron tranport chain,

22 tRNA and 2 rRNA.

Nucleoid

A compactd ma of DNA.

Mitochondrial DNA i

organizd into nucloid, ach

coniting of vral

mitochondrial gnom.

Mitochondrial F1

FoATP yntha, a rtary ezyme

embedded i the ier membrae that cpes prtpmpig t ATP sythesis, is essetia fr rma cristaestrctre65. This re i ier membrae strctreies a dimeric frm f ATP sythase that ctaisthe additia sbits e ad g. As isaized by eec-

tr micrscpy, the ATP sythase dimer has a dimericiterface with a sharp age that cd distrt the caipid membrae. This distrti might ctribte tthe high membrae cratre that characterizes cristaetbes66,67. Mgm1 is reqired fr the igmerizatif ATP sythase, pridig a ik betwee these twmdatrs f cristae strctre63.

Additia prteis mdate ier membraedyamics. I yeast, Mdm33 is reqired fr rmamitchdria mrphgy ad its erexpressi eadst septati ad esicati f the ier membraes68.Becase f these phetypes, Mdm33 has bee sggestedt hae a re i ier membrae fissi. Kckdw f

mitfii i mammaia ces cases dramatic abrm-aities f the cristae, restig i the frmati f cmpexayers f ier membrae69. Depeti f Mmm1,Mdm31 ad Mdm32 yeast prteis impicatedi mitochondrial (mt) DNA maiteace as caseaberrat cristae mrphgies70,71.

Biological functions of mitochondrial dynamics

Why d mitchdria ctiay fse ad diide?Recet stdies shw that these prcesses hae impr-tat cseqeces fr the mrphgy, fcti addistribti f mitchdria. First, fsi ad fissictr the shape, egth ad mber f mitchdria.The baace betwee these ppsig prcesses regatesmitchdria mrphgy. Secd, fsi ad fissiaw mitchdria t exchage ipid membraes aditramitchdria ctet. Sch exchage is crcia frmaitaiig the heath f a mitchdria ppati.Third, the shape f mitchdria affects the abiity fces t distribte their mitchdria t specific sb-cear catis. This fcti is especiay imprtat

i highy parized ces, sch as ers. Fiay, mit-chdria fissi faciitates apptsis by regatig thereease f itermembrae-space prteis it the cyts.As a rest f these cear fctis, mitchdriadyamics has cseqeces fr deepmet, diseasead apptsis.

Maintaining a healthy mitochondrial population.Mitchdria fsi is reqired t maitai a fc-tia mitchdria ppati i the ce. Fibrbaststhat ack bth MFn1 ad MFn2 hae redced respira-try capacity, ad idiida mitchdria shw greathetergeeity i shape ad membrae ptetia28. Cesthat ack oPA1 shw simiar defects, with a ee greaterredcti i respiratry capacity.

Hw des fsi prtect mitchdria fcti?It is prbabe that a primary fcti f mitchdriafsi is t eabe the exchage f ctets betweemitchdria (BOX 1). As a rest, mitchdria shdt be csidered atms rgaees; istead,the hdreds f mitchdria i a typica ce exist asa ppati f rgaees that cperate with eachther thrgh fsi ad fissi. The hetergeesprperties f mitchdria i fsi-deficiet cesare csistet with this mde28. I rma ces, a fewmitchdria might be -fctia wig t the ssf essetia cmpets. Hweer, this dysfcti is

trasiet becase mitchdria fsi prides a path-way fr these defectie mitchdria t regai essetiacmpets (FIG. 5a).

A essetia cmpet f mitchdria fcti ismitchdria DnA (mtDnA), which is rgaized itcmpact partices termed nucloid. The mtDnA gemeecdes essetia sbits f the respiratry cmpexesI, III ad Iv, ad is therefre essetia fr xidatie phs-phryati. Whe mitchdria fsi is abished,a arge fracti f the mitchdria ppati sesmtDnA ceids72. Drig mitchdria diisi irma ces, mst daghter mitchdria iherit ateast e mtDnA ceid73. Hweer, i cases where a

Figure 3 | md . | Mitochondrial fusionconsists of outer membrane (OM) fusion followed by inner

membrane (IM) fusion. Normally these events occur

coordinately. | The dynamin-related proteins Fzo1 and

Mgm1 are key molecules in the yeast mitochondrial fusion

machinery. Fzo1 is an integral outer membrane protein

with GTPase and heptad repeat domains that face the

cytoplasm. All of the domains are required for the fusion

activity of Fzo1. Mgm1 is present on the inner membrane,

facing the intermembrane space (IMS), and is

proteolytically processed by a rhomboid protease. Both

long (l-Mgm1) and short (s-Mgm1) forms are required for

mitochondrial fusion. In addition to inner membrane

fusion, Mgm1 is required for the maintenance of cristae

structures. Ugo1 binds to both Fzo1 and Mgm1 and

probably coordinates their function. All components are

encoded by nuclear DNA. The mitofusin proteins MFN1

and MFN2 are the mammalian homologues of Fzo1; OPA1

is the mammalian homologue of Mgm1. No mammalian

homologue of Ugo1 has been identified so far.

R E V I E W S

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a b

IM

OM

Fis1

Adaptor poteins(Mdv1, Caf4)

Dnm1

Dnm1

Chemotaxis

Th dirctd movmnt of cll

in rpon to a chmical

timulu.

daghter fais t iherit a ceid, mitchdria fsiwd eabe restrati f mtDnA. I fsi-deficietces, the ack f ctet exchage preets restratif mtDnA ceids ad prbaby accts fr thehetergeeity i membrae ptetia ad the redcedrespiratry capacity. It shd be ted that fsi-deficiet ces sti maitai sigificat mbers fmtDnA ceids; hweer, de t gig mitch-dria fissi, these ceids are ecased by a smamitchdria mass, ad therefre the fctia mit-chdria mass (at east i terms f bieergetics) i schces is greaty redced (FIG. 5b). I additi t mtDnA,it is as pssibe that ther cmpets, sch as sb-strates, metabites r specific ipids, ca be restred idefectie mitchdria by fsi. Frther stdies widetermie whether ctet exchage is the primaryfcti f mitchdria fsi. The imprtace fmitchdria fsi i deepmet ad disease mightbe a cseqece f this fcti.

Essential developmental functions. Pertrbatis imitchdria dyamics rest i specific deepmetadefects. Mice that ack either MFn1, MFn2 r oPA1 fait srie past mid-gestati6,74,75. MFn2 has a highy

specific fcti i the deepmet f the trphbastgiat ce ayer f the paceta6. likewise, MFn1 appearst hae a essetia paceta fcti72.

Mitchdria fissi is as a essetia prcess.Wrms that are deficiet i mitchdria diisi diebefre adthd76. A ifat patiet with a dmiat-egatie DRP1 aee has bee reprted. This patiet diedat ~1 mth f age ad had a wide rage f abrm-aities, icdig redced head grwth, icreased acticacid ad ptic atrphy. Fibrbasts frm this patietshwed egated mitchdria ad perxismes77.It is cear hw the deepmeta defects are reatedt these rgaear shape chages.

Mitochondrial distribution and recruitment in neurons.Gie the imprtace f mitchdria dyamics imaitaiig bieergetics, these dyamics are prbabya biqits pheme that is imprtat fr a ces.Hweer, certai ces, particary ers, seem t beespeciay depedet its prper ctr. This deped-ece f ers prbaby stems frm their high eergydemads ad the specia imprtace f prper mit-chdria distribti: mitchdria are ccetrated iseera era regis, icdig pre- ad pstsyapticsites13,17. T achiee this -ifrm distribti, ersrey heaiy actie trasprt t recrit mitchdriaad ther rgaees t ere termias3.

The prper caizati f mitchdria t axtermias depeds mitchdria dyamics. nersthat ack Mit, Mir r DRP1 shw defectie mit-chdria trasprt ad hae sparse mitchdria atax termias. Sch distribti defects ead t redcedcapacity fr syaptic trasmissi57,58,78. It seems ikeythat mitchdria that are caized t syapses areprimariy reqired t drie ATP-depedet prcesses.

The syapses f ers that express mtat DRP1 shwdefectie mbiizati f the resere esice p (a ATP-depedet prcess), ad the defects i syaptic trasmis-si ca be resced by experimetay fiig syapseswith ATP. I additi, syapse-caized mitchdriahep t regate Ca2+ hmestasis, athgh this fctiappears t be crcia y drig itese syaptic actiity.Syapses that ack Mir r DRP1 hae eeated restigCa2+ ees, bt rma Ca2+ dyamics are maitaiedexcept der sstaied ere stimati57,78.

Bth mitchdria fsi ad fissi affect themitchdria distribti i dedrites. I hippcampaers, mitchdria accmate at dedritic spiesfwig era stimati13. Ihibiti f mit-chdria fissi cases egati f the mitchdriaad decreases the abdace f dedritic mitchdria adthe desity f dedritic spies. Cersey, icreasedfissi faciitates the mbiizati f dedritic mitch-dria ad eads t a icreased spie mber 13. I thecerebem, the distribti f mitchdria i the de-dritic prcesses f Prkije ers is highy depedet mitchdria fsi72 (see bew).

Lymphocyte chemotaxis. Mitchdria dyamicsappears t be imprtat fr prper mitchdriaredistribti i ymphcytes drig chmotaxi79.Mitchdria are ccetrated i the traiig edge i

ymphcyte ce ies that migrate i respse t chemicaattractats. Mdati f mitchdria fsi rfissi affects bth mitchdria redistribti adce migrati. Fragmetati ehaces mitchdriaredistribti ad ce migrati, whereas cditis thatprmte fsi hae the ppsite effect. Therefre, as iers, mitchdria shape i ymphcytes ca affectthe recritmet f mitchdria t ca cear areas.

Regulation of apoptosis. I apptsis, seera strctrachages ccr i mitchdria drig the eary phase fce death (FIG. 6). The mitchdria becme fragmetedwig t icreased fissi actiity. At apprximatey the

Figure 4 | md . | In yeast, mitochondrial fission is mediated by the

dynamin-related protein Dnm1. Cytoplasmic Dnm1 localizes to the mitochondrial outer

membrane (OM), where it oligomerizes into a ring structure that constricts and severs the

mitochondrion. In this model, Dnm1 functions in an analogous manner to the way

dynamin functions in endocytosis. | The localization of Dnm1 on the mitochondrial outer

membrane is mediated by Fis1 and the adaptor proteins Mdv1 and Caf4. Fis1 is an integral

outer membrane protein that interacts with the N termini of Mdv1 and Caf4. Both Mdv1

and Caf4 have C-terminal WD-40 repeats that bind Dnm1. Fis1 and Dnm1 have

mammalian homologues (FIS1 and DRP1, respectively), but no Mdv1 or Caf4 homologues

have been identified so far. IM, inner membrane.

R E V I E W S



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a Wild-type cells b Fusion-deficient cells

Defectivemitochondrion

Rescuedmitochondrion

Fission

Fusion

Mitochondrial outer

membrane permeabilization

(MOMP). Th opning of por

in th mitochondrial outr

mmbran an arly vnt

during apoptoi that rla

apoptotic factor from th

mitochondrial intrmmbran

pac.

Haploinsufficiency

A gntic tat in diploid in

which a ingl functional copy

of a gn i inufficint to

maintain a normal phnotyp.

same time, mitochondrial outr mmbran prmabilization(MoMP) cases the reease f ctets f the iter-membrae space, sch as cytchrme c ad secdmitchdria-deried actiatr f caspase (SMAC)/Diab, it the cytpasm. Becase cytchrme c ispreferetiay seqestered i cristae cmpartmets,it is thght that the peig f cristae jctis isa ita step i faciitatig its efficiet reease. oce ithe cyts, cytchrme c actiates a cascade f caspasesthat prpagate ad execte the appttic prgramme.These three strctra chages fragmetati,MoMP ad cristae remdeig ccr at simiar

times, bt their tempra seqece ad casatie iksare sti ctrersia80,81.

Mitchdria fragmetati drig apptsis isassciated with dyamic chages i the mitchdriacaizati f seera prteis, icdig BAX, BAK,MFn2, edphii ad DRP1 (ReF. 81). Ihibiti ffissi actiity bcks mitchdria fragmetati,redces cytchrme c reease ad ca redce r deayce death depedig the experimeta system46,82,83.I Caenorhabditis elegans ad D. melanogaster, disrp-ti f DRP1 redces the mber f ce deaths8486.I mtipe systems, it seems that fissi is imprtatfr rapid ad efficiet ce death, athgh apptsis

ca ccr i the absece f mitchdria fissi. Aimprtat isse t rese i ftre stdies is hw fissiis reated t the permeabiizati f mitchdria.

Srprisigy, the appttic prteis BAX ad BAK,which hae we-estabished pr-appttic res imitchdria membrae permeabiizati, as appeart regate mitchdria mrphgy. BAX ad BAKdbe-kckt ces hae fragmeted mitchdriade t redced mitchdria fsi87, athgh theextet f this effect depeds the experimeta sys-tem88. litte is kw abt hw BAX ad BAK mediatetheir effects mitchdria mrphgy, bt BAXifeces MFn2 distribti the mitchdriater membrae87 ad BAK assciates with MFn1 adMFn2 (ReF. 88).

I cjcti with MoMP, remdeig f the cristaemembraes is reqired fr the rapid ad efficiet reeasef cytchrme c20,89. Mst cytchrme c is caized tcristae cmpartmets20; oPA1 appears t regate thediameter f cristae jctis ad therefre regatescytchrme c reease64,90. oerexpressi f oPA1

bcks cytchrme c reease fwig the idctif apptsis by maitaiig arrw cristae jctis64.DRP1 has as bee prpsed t pay a part i cristaeremdeig drig apptsis91.

Role in human disease

Seera hma diseases are cased by mtatis i geesthat are essetia fr mitchdria dyamics (TABLe 1).Each f these diseases cases degeerati f specificeres, reifrcig the ti that ers are particarypre t defects i mitchdria dyamics.

OPA1 and autosomal dominant optic atrophy.Heterzygs mtatis i oPA1 case atsmadmiat ptic atrphy (ADoA), the mst cmmheritabe frm f ptic erpathy92,93. This disease ischaracterized by the degeerati f retia gagices, the axs f which frm the ptic ere. Mre tha100 pathgeic oPA1 mtatis hae bee reprted,with mst ccrrig i the GTPase dmai94. Haf f themtats ecde a trcated prtei wig t a sesemtati. A few sese mtatis abish eary theetire cdig seqece, sggestig that haploinufficincyf oPA1 ca case ADoA. It remais pssibe that ther,ess seere, trcatis might hae dmiat-egatieactiity.

Hw these oPA1 mtatis case the ciica symp-

tms f ADoA remais t be carified. n-eraces frm patiets with ADoA ca hae aggregated, frag-meted r rma mitchdria93,95; hweer, becasedata frm y a few patiets hae bee reprted, it is tcear whether these fidigs are the rm. I additi,oPA1 mtatis hae bee assciated with redced ATPprdcti ad redced mtDnA ctet96,97. The defectsthat hae bee dcmeted i hma ADoA diseasedtisse are t as seere as thse bsered i experimetaces i which oPA1 is depeted. Fibrbasts that are defi-ciet fr oPA1 hae fragmeted mitchdria, defectsi respirati, aberrat cristae strctre ad icreasedssceptibiity t apptsis28,31,62,98.

Figure 5 | md d d . | In wild-type

cells, the vast majority of mitochondria are functional (shown in green). In this simplified

diagram, one mitochondrion is depicted as non-functional (shown in orange). One of

several possible reasons for dysfunction is a lack of mitochondrial DNA (mtDNA)

nucleoids (shown as black circles). The dysfunctional mitochondrion can regain its

function and mtDNA by fusing with a neighbouring mitochondrion. The fused

mitochondrion then undergoes fission, with both daughter mitochondria receiving

mtDNA nucleoids. It should be noted that the identities of the daughter mitochondria

are distinct from the parental mitochondria, owing to content exchange and the fact

that the fission point is typically distinct from the fusion point. | In fusion-deficient

cells, mitochondria are fragmented due to ongoing fission in the absence of fusion.

Mitochondria that lack mtDNA nucleoids accumulate because there is no pathway for

defective mitochondria to regain mtDNA. Fusion-deficient cells can maintain mtDNA

nucleoids, but such nucleoids serve a much smaller mitochondrial mass.

R E V I E W S

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Apoptoticstimuli

Cristae junctions

Cytochrome c

Sural nerve

A nory nrv innrvating

th calf and foot that i

commonly invtigatd by

biopy for th valuation of

priphral nuropathi.

Mse mdes f ADoA that ctai oPA1 mta-tis deep the featres f ADoA i a age-depedetmaer74,75. Heterzygs mice shw a prgressiedecie i retia gagi ce mber ad aberratisf axs i the ptic ere. Mice that are hmzygs frthe oPA1 mtati die at mid-gestati74,75, which is c-sistet with a essetia reqiremet fr mitchdriafsi drig embryic deepmet6.

MFN2 and Charcot-Marie-Tooth 2A. Charct-Marie-Tth (CMT) disease, e f the mst cmm heredi-tary erpathies, is cased by mtatis i at east 30differet gees99. Affected idiidas hae prgressiedista mtr ad sesry impairmets that start ithe feet ad hads as a rest f the degeerati f theg periphera eres. Depedig the type f CMT,these diseases are cased by either a primary defect ithe Schwa ces that myeiate the periphera eresr by a defect i the ers themsees99. CMT2A isa axpathy that is cased by the atter type f defect,ad it has bee assciated with >40 mtatis i MFn2.neary a f these disease aees ctai missese mta-tis r shrt, i-frame deetis100. Mst mtatiscster i r ear the GTPase dmai, bt sme as

ccr i each f the heptad repeat dmais f MFn2. Iadditi t the ss f periphera ere fcti, a sbsetf patiets with CMT2A hae ptic atrphy, sggestigthat oPA1 ad MFn2 mtatis ca ead t erappigciica tcmes101,102.

Becase f the difficties i stdyig ere tissefrm patiets, the pathgeic mechaisms that ead tperiphera ere degeerati i CMT2A are t wederstd. oy e stdy has reprted trastrctradefects i mitchdria frm the eres f patiets withCMT2A. Mitchdria i the ural nrv f tw patietsshwed strctra aberratis i their ter ad iermembraes, ag with sweig that is sggestie fmitchdria dysfcti103. Aggregati f mitch-dria was as bsered. Iterestigy, CMT2A aees fMFN2 (ReFs 27,104) case mitchdria aggregatiad sbseqet mitchdria trasprt defects iers104. Hweer, the mitchdria aggregatiphetype is depedet sigificat erexpressi27,ad therefre its reeace t disease pathgeesisremais t be carified.

Seera perpexig isses remai t be resed c-cerig the mecar geetics f CMT2A. Hw desmtati f e cpy fMFN2 ead t disease? Why areg periphera ers seectiey affected, gie thatMFn2 is a brady expressed prtei? Ces t theseisses hae cme frm aaysis f CMT2A aees imice27. May CMT2A aees fMfn2 are -fctiafr fsi whe expressed ae. Hweer, the fsiactiity f these -fctia aees ca be efficietycmpemeted by wid-type MFn1 (bt t MFn2).This cmpemetati is de t the abiity f MFn1 adMFn2 t frm heter-igmeric cmpexes that arefctia fr fsi. I a patiet with CMT2A, there-fre, ces that express MFn1 are prtected frm grssss f fsi actiity. By ctrast, ces with itte r MFn1 expressi sffer a greater reatie ss f fsiactiity. I part, these prperties f the CMT2A aeesmight derie the seectie ss f sesry ad mtrers. Csistet with this mde, MFn2 seems t bemre highy expressed i cetra ad periphera erstisse tha MFn1 (S.A.D. ad D.C.C., pbished bser-

atis). Ee i the periphera eres, it appears thatmitchdria fsi defects are y partia becase ythe gest eres are affected. Mst prbaby, the extremedimesis f the g periphera eres make them mst

erabe t chages i mitchdria dyamics.Hw might pertrbatis i mitchdria fsi

ead t erdegeerati? Ces t the pathgeicmechaisms hae cme frm the fidig that micethat ack MFn2 shw highy specific degeerati fPrkije ers i the cerebem, restig i cere-bear ataxia72. Prkije ces are the se efferet ersf the cerebem, ad they hae exqisitey frmed de-dritic prcesses. Bth deepig ad matre Prkijeces that se MFn2 fai t spprt dedritic tgrwth,particary that f dedritic spies, which are the sites fsyaptic cectis. I rma Prkije ces, abdattbar mitchdria reside i dedritic prcesses. Byctrast, mtat Prkije ces hae fragmeted mit-chdria that fai t distribte effectiey ag dedritic

Figure 6 | md d d . At an early stage of apoptosis,

three structural changes occur in mitochondria. Fragmentation takes place as a result of

increased fission mediated by dynamin-related protein-1 (DRP1) and the mitochondrial

fission-1 protein (FIS1). Mitochondrial outer membrane permeabilization (MOMP;

indicated by dashed outlines) is induced by the pro-apoptotic BCL2-family members BAX

and BAK. MOMP enables the release of cytochrome c (shown as red dots) and other soluble

proteins from the intermembrane space. However, release of cytochromec is efficient only

if the cristae junctions are widened to allow escape from the cristae compartments. The

dynamin-related proteins OPA1 and DRP1 have been implicated in cristae remodelling.

Table 1 | Disorders associated with mitochondrial perturbations

D md

g D

CMT2A Fusion MFN2 Autosomal dominantperipheral neuropathy

ADOA Fusion OPA1 Autosomal dominant opticatrophy (ADOA)

CMT4A Fission? GDAP1 Autosomal recessiveperipheral neuropathy

Unnamed Fission DRP1 Neonatal lethality

CMT, Charcot-Marie-Tooth; DRP1, dynamin-related protein-1; GDAP1, ganglioside-induceddifferentiation-associated protein-1; MFN2, mitofusin-2; OPA1, optic atrophy-1.

R E V I E W S

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=OMIM&dopt=DocSum&list_uids=609260%2C118210http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=OMIM&dopt=DocSum&list_uids=609260%2C118210


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prcesses. I additi, the Prkije ces shw a ss frespiratry actiity, prbaby wig t a accmatif mitchdria that ack mtDnA ceids. Therefre,ss f mitchdria fsi i Prkije ers impairsrespiratry actiity ad mitchdria caizati.

GDAP1 and Charcot-Marie-Tooth 4A.Ather frm fCMT is assciated with defects i mitchdria dy-amics. Gagiside-idced differetiati-assciatedprtei-1 (GDAP1) is mtated i CMT4A, e f thefew recessie frms f CMT disease. CMT4A has bthdemyeiatig ad axa featres ad, csistet withthis mixed ciica presetati, GDAP1 is expressedi bth Schwa ces ad ers105. GDAP1 is aitegra ter membrae prtei that prbaby affectsmitchdria diisi105. Disease aees either fai tcaize t mitchdria r are defectie i stimatigmitchdria fissi whe erexpressed105. If GDAP1disease aees disrpt rma mitchdria fissi,they might case mitchdria distribti defectssimiar t thse that are idced by the DRP1 mtatis

discssed abe13,78.

Perspectives

The stdy f mitchdria dyamics has dergegreat adaces i the past few years. It is w cear thatmitchdria dyamics is imprtat fr the fctiastate f mitchdria. By eabig ctet exchagebetwee mitchdria, fsi ad fissi preet theaccmati f defectie mitchdria. These pps-ig prcesses as ctr mitchdria shape, whichaffects the distribti f mitchdria as we as theirparticipati i apptsis. As a rest, mitchdriadyamics is particary imprtat i ces ad tissesthat hae a specia depedece mitchdria fc-ti. Defects i mitchdria dyamics ca maifest imammaia deepmet, apptsis ad disease. As rkwedge f mitchdria dyamics icreases, we caexpect t ear abt its iemet i ther prcesses.The ik betwee defects i mitchdria fsi aderdegeeratie disease is particary itrigig. Iftre stdies, the pathphysigica mechaisms thatderie erdegeeratie diseases sch as ADoA adCMT2A wi hpefy be frther dissected i apprpriate

aima mdes.

1. Chan, D. C. Mitochondrial fusion and fission in

mammals.Annu. Rev. Cell Dev. Biol.22, 7999

(2006).2. Okamoto, K. & Shaw, J. M. Mitochondrial morphology

and dynamics in yeast and multicellular eukaryotes.

Annu. Rev. Genet.39, 50336 (2005).3. Hollenbeck, P. J. & Saxton, W. M. The axonal

transport of mitochondria.J. Cell Sci. 118,

54115419 (2005).

4. Nunnari, J. et al. Mitochondrial transmission during

mating in Saccharomyces cerevisiae is determined by

mitochondrial fusion and fission and the

intramitochondrial segregation of mitochondrial DNA.

Mol. Biol. Cell8, 12331242 (1997).

5. Bleazard, W. et al. The dynamin-related GTPase Dnm1

regulates mitochondrial fission in yeast. Nature Cell

Biol.1, 298304 (1999).6. Chen, H. et al. Mitofusins Mfn1 and Mfn2

coordinately regulate mitochondrial fusion and are

essential for embryonic development.J. Cell Biol.160,

189200 (2003).

7. Sesaki, H. & Jensen, R. E. Division versus fusion:

Dnm1p and Fzo1p antagonistically regulate

mitochondrial shape.J. Cell Biol.147, 699706

(1999).

8. Smirnova, E., Griparic, L., Shurland, D. L. &

van der Bliek, A. M. Dynamin-related protein Drp1 is

required for mitochondrial division in mammalian

cells. Mol. Biol. Cell12, 22452256 (2001).

9. Hales, K. G. & Fuller, M. T. Developmentally regulated

mitochondrial fusion mediated by a conserved, novel,

predicted GTPase. Cell90, 121129 (1997).

This study identified the first component of the

mitochondrial fusion machinery, thereby providing

an avenue to identify new components in further

yeast genetic screens.

10. Fehrenbacher, K. L., Yang, H. C., Gay, A. C.,Huckaba, T. M. & Pon, L. A. Live cell imaging of

mitochondrial movement along actin cables in

budding yeast. Curr. Biol.14, 19962004 (2004).

11. Morris, R. L. & Hollenbeck, P. J. Axonal transport of

mitochondria along microtubules and F-actin in living

vertebrate neurons.J. Cell Biol.131, 13151326

(1995).12. Ligon, L. A. & Steward, O. Role of microtubules and

actin filaments in the movement of mitochondria in

the axons and dendrites of cultured hippocampal

neurons.J. Comp. Neurol.427, 351361 (2000).

13. Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M.

The importance of dendritic mitochondria in the

morphogenesis and plasticity of spines and synapses.

Cell119, 873887 (2004).

14. Miller, K. E. & Sheetz, M. P. Axonal mitochondrial

transport and potential are correlated.J. Cell Sci.

117, 27912804 (2004).

15. Pilling, A. D., Horiuchi, D., Lively, C. M. & Saxton, W. M.

Kinesin-1 and dynein are the primary motors for fast

transport of mitochondria in Drosophila motor axons.

Mol. Biol. Cell17, 20572068 (2006).

16. Morris, R. L. & Hollenbeck, P. J. The regulation of

bidirectional mitochondrial transport is coordinated

with axonal outgrowth.J. Cell Sci. 104, 917927

(1993).

17. Chang, D. T., Honick, A. S. & Reynolds, I. J.

Mitochondrial trafficking to synapses in cultured

primary cortical neurons.J. Neurosci.26,

70357045 (2006).

18. Chada, S. R. & Hollenbeck, P. J. Nerve growth factor

signaling regulates motility and docking of axonal

mitochondria. Curr. Biol.14, 12721276 (2004).

19. Mannella, C. A. Structure and dynamics of the

mitochondrial inner membrane cristae. Biochim.Biophys. Acta1763, 542548 (2006).

20. Scorrano, L. et al. A distinct pathway remodels

mitochondrial cristae and mobilizes cytochrome c

during apoptosis. Dev. Cell2, 5567 (2002).

21. Gilkerson, R. W., Selker, J. M. & Capaldi, R. A.

The cristal membrane of mitochondria is the principal

site of oxidative phosphorylation. FEBS Lett.546,

355358 (2003).

22. Vogel, F., Bornhovd, C., Neupert, W. & Reichert, A. S.

Dynamic subcompartmentalization of the

mitochondrial inner membrane.J. Cell Biol.175,

237247 (2006).

23. Wurm, C. A. & Jakobs, S. Differential protein

distributions define two sub-compartments of the

mitochondrial inner membrane in yeast. FEBS Lett.

580, 56285634 (2006).

24. Hermann, G. J. et al. Mitochondrial fusion in yeast

requires the transmembrane GTPase Fzo1p.J. Cell

Biol.143, 359373 (1998).

25. Shaw, J. M. & Nunnari, J. Mitochondrial dynamics anddivision in budding yeast. Trends Cell Biol.12,

178184 (2002).

26. Meeusen, S., McCaffery, J. M. & Nunnari, J.

Mitochondrial fusion intermediates revealed in vitro.

Science305, 17471752 (2004).

This study described an in vitro fusion assay that

identifies mitochondrial fusion intermediates.27. Detmer, S. A. & Chan, D. C. Complementation

between mouse Mfn1 and Mfn2 protects

mitochondrial fusion defects caused by CMT2A

disease mutations.J. Cell Biol.176, 405414 (2007).

28. Chen, H., Chomyn, A. & Chan, D. C. Disruption of

fusion results in mitochondrial heterogeneity and

dysfunction.J. Biol. Chem.280, 2618526192

(2005).

29. Koshiba, T. et al. Structural basis of mitochondrial

tethering by mitofusin complexes. Science305,

858862 (2004).

30. Meeusen, S. et al. Mitochondrial inner-membrane

fusion and crista maintenance requires the dynamin-

related GTPase Mgm1. Cell127, 383395 (2006).31. Cipolat, S., Martins de Brito, O., Dal Zilio, B. &

Scorrano, L. OPA1 requires mitofusin 1 to promote

mitochondrial fusion. Proc. Natl Acad. Sci. USA101,

1592715932 (2004).

32. Legros, F., Lombes, A., Frachon, P. & Rojo, M.

Mitochondrial fusion in human cells is efficient,

requires the inner membrane potential, and is

mediated by mitofusins. Mol. Biol. Cell13,

43434354 (2002).

33. Malka, F. et al. Separate fusion of outer and inner

mitochondrial membranes. EMBO Rep.6, 853859

(2005).

34. Ishihara, N., Fujita, Y., Oka, T. & Mihara, K. Regulation

of mitochondrial morphology through proteolyticcleavage of OPA1. EMBO J.25, 29662977 (2006).

35. Altmann, K. & Westermann, B. Role of essential genes

in mitochondrial morphogenesis in Saccharomyces

cerevisiae. Mol. Biol. Cell16, 54105417 (2005).

36. Dimmer, K. S. et al. Genetic basis of mitochondrial

function and morphology in Saccharomyces

cerevisiae. Mol. Biol. Cell13, 847853 (2002).

37. Choi, S. Y. et al. A common lipid links Mfn-mediated

mitochondrial fusion and SNARE-regulated exocytosis.

Nature Cell Biol.8, 12551262 (2006).38. Fratti, R. A., Jun, Y., Merz, A. J., Margolis, N. &

Wickner, W. Interdependent assembly of specific

regulatory lipids and membrane fusion proteins into

the vertex ring domain of docked vacuoles.J. Cell Biol.

167, 10871098 (2004).

39. Vitale, N. et al. Phospholipase D1: a key factor for the

exocytotic machinery in neuroendocrine cells.

EMBO J.20, 24242434 (2001).

40. Ingerman, E. et al. Dnm1 forms spirals that are

structurally tailored to fit mitochondria.J. Cell Biol.170, 10211027 (2005).

41. Bhar, D., Karren, M. A., Babst, M. & Shaw, J. M.

Dimeric Dnm1-G385D interacts with Mdv1 on

mitochondria and can be stimulated to assemble into

fission complexes containing Mdv1 and Fis1.J. Biol.

Chem.281, 1731217320 (2006).

42. Fekkes, P., Shepard, K. A. & Yaffe, M. P. Gag3p,

an outer membrane protein required for fission of

mitochondrial tubules.J. Cell Biol.151, 333340

(2000).43. Mozdy, A. D., McCaffery, J. M. & Shaw, J. M. Dnm1p

GTPase-mediated mitochondrial fission is a multi-step

process requiring the novel integral membrane

component Fis1p.J. Cell Biol.151, 367380 (2000).44. Tieu, Q. & Nunnari, J. Mdv1p is a WD repeat protein

that interacts with the dynamin-related GTPase,

Dnm1p, to trigger mitochondrial division.J. Cell Biol.

151, 353366 (2000).

R E V I E W S

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54332&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=214400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=214400http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54332&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


10/10

References 4244 showed the power of yeast

genetic screens for identifying essential

components of the mitochondrial fission machinery.45. Griffin, E. E., Graumann, J. & Chan, D. C. The WD40

protein Caf4p is a component of the mitochondrial

fission machinery and recruits Dnm1p to

mitochondria.J. Cell Biol.170, 237248 (2005).

46. Lee, Y. J., Jeong, S. Y., Karbowski, M., Smith, C. L. &

Youle, R. J. Roles of the mammalian mitochondrial

fission and fusion mediators Fis1, Drp1, and Opa1 in

apoptosis. Mol. Biol. Cell15, 50015011 (2004).

47. Koch, A. et al. Dynamin-like protein 1 is involved inperoxisomal fission.J. Biol. Chem.278, 85978605

(2003).

48. Koch, A., Yoon, Y., Bonekamp, N. A., McNiven, M. A.

& Schrader, M. A role for Fis1 in both mitochondrial

and peroxisomal fission in mammalian cells. Mol. Biol.

Cell16, 50775086 (2005).

49. Escobar-Henriques, M., Westermann, B. & Langer, T.

Regulation of mitochondrial fusion by the F-box

protein Mdm30 involves proteasome-independent

turnover of Fzo1.J. Cell Biol.173, 645650 (2006).

50. Neutzner, A. & Youle, R. J. Instability of the mitofusin

Fzo1 regulates mitochondrial morphology during the

mating response of the yeast Saccharomyces

cerevisiae.J. Biol. Chem.280, 1859818603

(2005).

51. Karbowski, M., Neutzner, A. & Youle, R. J.

The mitochondrial E3 ubiquitin ligase MARCH5 is

required for Drp1 dependent mitochondrial division.

J. Cell Biol.178, 7184 (2007).

52. Nakamura, N., Kimura, Y., Tokuda, M., Honda, S. &

Hirose, S. MARCH-V is a novel mitofusin 2- and

Drp1-binding protein able to change mitochondrial

morphology. EMBO Rep.7, 10191022 (2006).

53. Eura, Y., Ishihara, N., Oka, T. & Mihara, K.

Identification of a novel protein that regulates

mitochondrial fusion by modulating mitofusin (Mfn)

protein function.J. Cell Sci.119, 49134925 (2006).

54. Wasiak, S., Zunino, R. & McBride, H. M. Bax/Bak

promote sumoylation of DRP1 and its stable

association with mitochondria during apoptotic cell

death.J. Cell Biol.177, 439450 (2007).55. Taguchi, N., Ishihara, N., Jofuku, A., Oka, T. &

Mihara, K. Mitotic phosphorylation of dynamin-related

GTPase Drp1 participates in mitochondrial fission.

J. Biol. Chem.282, 1152111529 (2007).

56. Meisinger, C. et al. The morphology proteins Mdm12/

Mmm1 function in the major -barrel assemblypathway of mitochondria. EMBO J.26, 22292239

(2007).

57. Guo, X. et al. The GTPase dMiro is required for axonal

transport of mitochondria to Drosophila synapses.Neuron47, 379393 (2005).

58. Stowers, R. S., Megeath, L. J., Gorska-Andrzejak, J.,

Meinertzhagen, I. A. & Schwarz, T. L. Axonal transport

of mitochondria to synapses depends on milton, a

novel Drosophila protein. Neuron36, 10631077

(2002).

59. Glater, E. E., Megeath, L. J., Stowers, R. S. &

Schwarz, T. L. Axonal transport of mitochondria

requires milton to recruit kinesin heavy chain and is

light chain independent.J. Cell Biol.173, 545557

(2006).60. Frederick, R. L., McCaffery, J. M., Cunningham, K. W.,

Okamoto, K. & Shaw, J. M. Yeast Miro GTPase,

Gem1p, regulates mitochondrial morphology via a

novel pathway.J. Cell Biol.167, 8798 (2004).

61. Sesaki, H., Southard, S. M., Yaffe, M. P. & Jensen, R. E.

Mgm1p, a dynamin-related GTPase, is essential for

fusion of the mitochondrial outer membrane.

Mol. Biol. Cell14, 23422356 (2003).

62. Olichon, A. et al. Loss of OPA1 perturbates themitochondrial inner membrane structure and integrity,

leading to cytochrome c release and apoptosis.J. Biol.

Chem.278, 77437746 (2003).

63. Amutha, B., Gordon, D. M., Gu, Y. & Pain, D. A novel

role of Mgm1p, a dynamin-related GTPase, in ATP

synthase assembly and cristae formation/

maintenance. Biochem. J.381, 1923 (2004).

64. Frezza, C. et al. OPA1 controls apoptotic cristae

remodeling independently from mitochondrial fusion.

Cell126, 177189 (2006).

65. Paumard, P. et al. The ATP synthase is involved in

generating mitochondrial cristae morphology.

EMBO J.21, 221230 (2002).

66. Minauro-Sanmiguel, F., Wilkens, S. & Garcia, J. J.

Structure of dimeric mitochondrial ATP synthase:

novel F0

bridging features and the structural basis of

mitochondrial cristae biogenesis. Proc. Natl Acad. Sci.

USA102, 1235612358 (2005).

67. Dudkina, N. V., Heinemeyer, J., Keegstra, W.,

Boekema, E. J. & Braun, H. P. Structure of dimeric

ATP synthase from mitochondria: an angular

association of monomers induces the strong curvature

of the inner membrane. FEBS Lett.579, 57695772

(2005).

68. Messerschmitt, M. et al. The inner membrane protein

Mdm33 controls mitochondrial morphology in yeast.

J. Cell Biol.160, 553564 (2003).69. John, G. B. et al. The mitochondrial inner membrane

protein mitofilin controls cristae morphology.

Mol. Biol. Cell16, 15431554 (2005).70. Hobbs, A. E., Srinivasan, M., McCaffery, J. M. &

Jensen, R. E. Mmm1p, a mitochondrial outer

membrane protein, is connected to mitochondrial

DNA (mtDNA) nucleoids and required for mtDNA

stability.J. Cell Biol.152, 401410 (2001).

71. Dimmer, K. S., Jakobs, S., Vogel, F., Altmann, K. &

Westermann, B. Mdm31 and Mdm32 are inner

membrane proteins required for maintenance of

mitochondrial shape and stability of mitochondrial DNA

nucleoids in yeast.J. Cell Biol.168, 103115 (2005).

72. Chen, H., McCaffery, J. M. & Chan, D. C.

Mitochondrial fusion protects against

neurodegeneration in the cerebellum. Cell130,

548562 (2007).

This study showed that mitochondrial fusion is

essential for respiratory function and that it

protects neurons in the cerebellum from

degeneration findings that will probably be

relevant for understanding CMT2A pathogenesis.

73. Legros, F., Malka, F., Frachon, P., Lombes, A. &

Rojo, M. Organization and dynamics of human

mitochondrial DNA.J. Cell Sci. 117, 26532662

(2004).

74. Alavi, M. V. et al. A splice site mutation in the murine

Opa1 gene features pathology of autosomal dominant

optic atrophy. Brain130, 10291042 (2007).

75. Davies, V. J. et al. Opa1 deficiency in a mouse model

of autosomal dominant optic atrophy impairs

mitochondrial morphology, optic nerve structure and

visual function. Hum. Mol. Genet.16, 13071318

(2007).76. Labrousse, A. M., Zappaterra, M. D., Rube, D. A. &

van der Bliek, A. M. C. elegans dynamin-related

protein DRP-1 controls severing of the mitochondrial

outer membrane. Mol. Cell4, 815826 (1999).77. Waterham, H. R. et al. A lethal defect of mitochondrial

and peroxisomal fission. N. Engl. J. Med.356,

17361741 (2007).

This study provided clinical evidence for the

essentiality of mitochondrial fission.

78. Verstreken, P. et al. Synaptic mitochondria are criticalfor mobilization of reserve pool vesicles at Drosophila

neuromuscular junctions. Neuron47, 365378

(2005).

79. Campello, S. et al. Orchestration of lymphocyte

chemotaxis by mitochondrial dynamics.J. Exp. Med.

203, 28792886 (2006).

80. Arnoult, D. Mitochondrial fragmentation in apoptosis.

Trends Cell Biol.17, 612 (2007).81. Youle, R. J. & Karbowski, M. Mitochondrial fission in

apoptosis. Nature Rev. Mol. Cell Biol.6, 657663

(2005).82. Frank, S. et al. The role of dynamin-related protein 1,

a mediator of mitochondrial fission, in apoptosis.

Dev. Cell1, 515525 (2001).

This study provided the first evidence that

mitochondrial fission has a significant role in

apoptosis.

83. Parone, P. A. et al. Inhibiting the mitochondrial fission

machinery does not prevent Bax/Bak-dependent

apoptosis. Mol. Cell. Biol.26, 73977408 (2006).84. Abdelwahid, E. et al. Mitochondrial disruption in

Drosophila apoptosis. Dev. Cell12, 793806 (2007).

85. Goyal, G., Fell, B., Sarin, A., Youle, R. J. & Sriram, V.

Role of mitochondrial remodeling in programmed cell

death in Drosophila melanogaster. Dev. Cell12,

807816 (2007).

86. Jagasia, R., Grote, P., Westermann, B. & Conradt, B.

DRP-1-mediated mitochondrial fragmentation during

EGL-1-induced cell death in C. elegans. Nature433,

754760 (2005).

87. Karbowski, M., Norris, K. L., Cleland, M. M., Jeong,

S. Y. & Youle, R. J. Role of Bax and Bak in

mitochondrial morphogenesis. Nature443, 658662

(2006).

88. Brooks, C. et al. Bak regulates mitochondrial

morphology and pathology during apoptosis by

interacting with mitofusins. Proc. Natl Acad. Sci. USA

104, 1164911654 (2007).

89. Goldstein, J. C., Waterhouse, N. J., Juin, P., Evan, G. I.

& Green, D. R. The coordinate release of cytochrome c

during apoptosis is rapid, complete and kinetically

invariant. Nature Cell Biol.2, 156162 (2000).

90. Cipolat, S. et al. Mitochondrial rhomboid PARL

regulates cytochrome c release during apoptosis via

OPA1-dependent cristae remodeling. Cell126,

163175 (2006).

91. Germain, M., Mathai, J. P., McBride, H. M. &

Shore, G. C. Endoplasmic reticulum BIK initiates

DRP1-regulated remodelling of mitochondrial cristae

during apoptosis. EMBO J.24, 15461556 (2005).92. Alexander, C. et al.OPA1, encoding a dynamin-related

GTPase, is mutated in autosomal dominant optic

atrophy linked to chromosome 3q28. Nature Genet.

26, 211215 (2000).93. Delettre, C. et al. Nuclear gene OPA1, encoding a

mitochondrial dynamin-related protein, is mutated in

dominant optic atrophy. Nature Genet.26, 207210

(2000).

References 92 and 93 showed that dominant optic

atrophy is caused by mutations in OPA1.

94. Ferre, M., Amati-Bonneau, P., Tourmen, Y., Malthiery, Y.

& Reynier, P. eOPA1: an online database for OPA1

mutations. Hum. Mutat.25, 423428 (2005).

95. Olichon, A. et al. Effects of OPA1 mutations on

mitochondrial morphology and apoptosis: relevance to

ADOA pathogenesis.J. Cell Physiol. 211, 423430

(2006).

96. Kim, J. Y. et al. Mitochondrial DNA content is

decreased in autosomal dominant optic atrophy.

Neurology64, 966972 (2005).

97. Lodi, R. et al. Deficit ofin vivo mitochondrial ATP

production in OPA1-related dominant optic atrophy.

Ann. Neurol.56, 719723 (2004).

98. Griparic, L., van der Wel, N. N., Orozco, I. J., Peters, P. J.

& van der Bliek, A. M. Loss of the intermembrane space

protein Mgm1/OPA1 induces swelling and localized

constrictions along the lengths of mitochondria.J. Biol.

Chem.279, 1879218798 (2004).99. Zuchner, S. & Vance, J. M. Mechanisms of disease:

a molecular genetic update on hereditary axonal

neuropathies. Nature Clin. Pract. Neurol.2, 4553

(2006).

100. Zuchner, S. et al. Mutations in the mitochondrial GTPase

mitofusin 2 cause Charcot-Marie-Tooth neuropathy

type 2A. Nature Genet.36, 449451 (2004).

This study showed that mutations in MFN2 cause

the peripheral neuropathy CMT2A.

101. Zuchner, S. et al. Axonal neuropathy with optic

atrophy is caused by mutations in mitofusin 2.

Ann. Neurol.59, 276281 (2006).

102. Chung, K. W. et al. Early onset severe and late-onsetmild Charcot-Marie-Tooth disease with mitofusin 2

(MFN2) mutations. Brain129, 21032118 (2006).

103.Verhoeven, K.et al.MFN2 mutation distribution and

genotype/phenotype correlation in Charcot-Marie-Tooth

type 2. Brain129, 20932102 (2006).

104. Baloh, R. H., Schmidt, R. E., Pestronk, A. &

Milbrandt, J. Altered axonal mitochondrial transport

in the pathogenesis of Charcot-Marie-Tooth disease

from mitofusin 2 mutations.J. Neurosci.27,

422430 (2007).

105. Niemann, A., Ruegg, M., La Padula, V., Schenone, A. &

Suter, U. Ganglioside-induced differentiation

associated protein 1 is a regulator of the mitochondrial

network: new implicat ions for Charcot-Marie-Tooth

disease.J. Cell Biol.170, 10671078 (2005).

AcknowledgementsThis work was supported by grants from the National

Institutes of Health. D.C.C. is an Ellison Medical Foundation

Senior Scholar in Aging.

DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=gene

BAK |BAX |Dnm1 | DRP1|FIS1|FZO |Fzo1 | GDAP1|Gem1 |

MARCH5 |MDM10 |MDM12|Mdm30 |Mdm31 | Mdm32 |

Mdm33 | MFN1 | MFN2|Mgm1|milton |Miro |MMM1 |NGF|

OPA1 | SMAC|TIM23 | Ugo1

OMIM:http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=OMIM

CMT2A |CMT4A

FURTHER INFORMATIONDavid C. Chans homepage:

http://www.its.caltech.edu/~chanlab

all links are active in the online pDf

R E V I E W S

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=578&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=581&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=581&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=850686&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=850686&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10059&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10059&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51024&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51024&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51024&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=42745&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=42745&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=852477&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=852477&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54332&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54332&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=851249&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=851249&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54708&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=851223&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=854153&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=854153&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=854153&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=851083&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=851083&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=856601&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=856601&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=854318&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=852002&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToS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Funciones y Disfunciones de La Dinamica Mitocondrial 2007

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