malate aspartate shuttle

8/9/2019 Malate Aspartate Shuttle

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The malate-aspartate shuttle (sometimes also the malate shuttle) is a biochemical

system for translocating electrons produced during glycolysis across the

semipermeable inner membrane of the mitochondrion for oxidative phosphorylation

in eukaryotes. These electrons enter the electron transport chain of the

mitochondria via reduction equivalents to generate ATP. The shuttle system is

required because the mitochondrial inner membrane is impermeable to A!"# theprimary reducing equivalent of the electron transport chain. To circumvent this#

malate carries the reducing equivalents across the membrane.


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Mechanism

The primary en$yme in the malate-aspartate shuttle is malate dehydrogenase.

%alate dehydrogenase is present in t&o forms in the shuttle system' mitchondrial

malate dehydrogenase and cytosolic malate dehydrogenase. The t&o malate

dehydrogenases are dierentiated by their location and structure# and cataly$e their

reactions in opposite directions in this process.

irst# in the cytosol# malate dehydrogenase catalyses the reaction of oxaloacetate

and A!" to produce malate and A!*. +n this process# t&o electrons generated

from A!"# and an accompanying "*# are attached to oxaloacetate to form malate.

,nce malate is formed# the rst antiporter (malate-alpha-ketoglutarate) imports the

malate from the cytosol into the mitochondrial matrix and also exports alpha-

ketoglutarate from the matrix into the cytosol simultaneously. After malate reaches

the mitochondrial matrix# it is converted by mitochondrial malate dehydrogenase

into oxaloacetate# during &hich A!* is reduced &ith t&o electrons to form A!"

and an "* is released. ,xaloacetate is then transformed into aspartate (since

oxaloacetate cannot be transported into the cytosol) by mitochondrial aspartate

aminotransferase. ince aspartate is an amino acid# an amino radical needs to be

added to the oxaloacetate. This is supplied by glutamate# &hich in the process is

transformed into alpha-ketoglutarate by the same en$yme.

The second antiporter (the glutamate-aspartate antiporter) imports glutamate from

the cytosol into the matrix and exports aspartate from the matrix to the cytosol.

,nce in the cytosol# aspartate is converted by cytosolic aspartate aminotransferase

to oxaloacetate.

The net eect of the malate-aspartate shuttle is purely redox' A!" in the cytosol is

oxidi$ed to A!*# and A!* in the matrix is reduced to A!". The A!* in the

cytosol can then be reduced again by another round of glycolysis# and the A!" in

the matrix can be used to pass electrons to the electron transport chain so ATP can

be synthesi$ed.

ince the malate-aspartate shuttle regenerates A!" inside the mitochondrial

matrix# it is capable of maximi$ing the number of ATPs produced in glycolysis

(/0A!")# ultimately resulting in a net gain of /1 ATP molecules per molecule of

glucose metaboli$ed. 2ompare this to the glycerol /-phosphate shuttle# &hich

reduces A!* to produce A!"3# donates electrons to the quinone pool in the

electron transport chain# and is capable of generating only 3 ATPs per A!"

generated in glycolysis (ultimately resulting in a net gain of /4 ATPs per glucose

metaboli$ed). (These ATP numbers are prechemiosmotic# and should be reduced in

light of the &ork of %itchell and many others. 5ach A!" produced only 3.6 ATPs#

and each A!"3 produces only 7.6 ATPs. "ence# the ATPs per glucose should be


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reduced to /3 from /1 and /8 from /4. +t should also be noted that the extra "*

required to bring in the inorganic phosphate during ,xidative-Phosphorylation

contributes to the /8 and /3 numbers as &ell).

Synaptic mitochondria in synaptictransmission and organization of vesicle poolsin health and disease

Cell types rich in mitochondria, including neurons, display a high energy demand and aneed for calcium buffering. The importance of mitochondria for proper neuronal

function is stressed by the occurrence of neurological defects in patients suffering from a

great variety of diseases caused by mutations in mitochondrial genes. Genetic and

pharmacological evidence also reveal a role of these organelles in various aspects of

neuronal physiology and in the pathogenesis of neurodegenerative disorders. Yet the

mechanisms by which mitochondria can affect neurotransmission largely remain to be

elucidated. In this review we focus on eperimental data that suggest a critical function

of synaptic mitochondria in the function and organization of synaptic vesicle pools, and

in neurotransmitter release during intense neuronal activity. !e discuss how calcium

handling, "T# production and other mitochondrial mechanisms may influence synaptic

vesicle pool organization and synaptic function. Given the lin$ between synaptic

mitochondrial function and neuronal communication, efforts toward better

understanding mitochondrial biology may lead to novel therapeutic approaches of

neurological disorders including "lzheimer%s disease, #ar$inson%s disease, amyotrophic

lateral sclerosis and psychiatric disorders that are at least in part caused by

mitochondrial deficits.

&itochondria are dynamic organelles that divide, fuse and are redistributed within the

cell in response to various physiological cues. 'esides their predominant role in energy

metabolism ()igure*+, they are involved in many other cellular processes that are also

relevant for neuronal function, including the regulation of calcium homeostasis and a

form of programmed cell death (or apoptosis+. efects in all these functions as well as in

mitochondrial fusion or fission are predicted to affect various aspects of neuronal
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physiology (i&auro and Schon, -/0 Chen and Chan, -1+. 2owever, unraveling

the lin$ between a mitochondrial defect and its conse3uences on neuronal function or

survival has proven a comple tas$, mostly because different mitochondrial functions

are interdependent (see for eample 4iemann et al., -50Graier et al., -60 Gunter

and Sheu, -1see also below+. 7perimental results obtained using drugs or mutationsthat interfere with one aspect of mitochondrial physiology thus need to be interpreted

with care, as they may have numerous side effects.

Mitochondrial functions susceptible to affect neurotransmission. Schematic representation of

a mitochondrion illustrating the different mitochondrial functions discussed in the tet. (*+ &itochondria

are dynamic organelles, able to move bidirectionally along microtubules tracts with the help of motor

proteins ($inesin for anterograde and dynein for retrograde aonal transport, respectively+ and adaptor

proteins (e.g., &ilton and the associated 8ho9GT#ase &iro or syntabulin+. Short9distance transport along

actin filaments is mediated by myosin motors (not shown+. (-+ The :rebs cycle ta$es place in the

mitochondrial matri, generating ;9$etoglutarate and electron donors (4"2 and succinate+. (ligomycin

is an inhibitor of the "T# synthase. (?+ &itochondria are also involved in calcium homeostasis, and

Ca

-B

ions can be se3uestered in the matri under the form of a reversible phosphate comple. !hile theouter mitochondrial membrane is rather permeable to calcium, Ca-Bentry across the inner mitochondrial

membrane is mediated by a uniporter, and its etrusion largely relies on a sodiumcalcium echanger.

&itochondrial calcium transport can be inhibited by T##B(tetraphenylphosphonium+.
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This review focuses on the role of presynaptic mitochondria in the control of synaptic vesicle

(SA+ function. In general, SAs can be attributed to three functionally different pools, termed the

readily releasable pool, the recycling pool and the reserve pool (8#+ (8izzoli and 'etz, -5+.

Together, the readily releasable pool and the recycling pool, sometimes referred to as the eo9

endo cycling pool (7C#+, typically represent about *@-D of the SAs and are released under

moderate or intense neuronal activity, whereas vesicles from the 8# are recruited only uponhigh fre3uency stimulation ()igure -+ (:uromi and :ido$oro, -508izzoli and 'etz, -5+.

'ased on these characteristics, different stimulation protocols have been developed that allow

the specific mobilization of SAs from different pools as well as their labeling with fluorescent

dyes (:uromi and :ido$oro, --0Aerstre$en et al., -/+. 'ecause the synaptic vesicle cycle

involves numerous "T#9consuming steps and is tightly controlled by the cytosolic calcium

concentration (ECa-BFcyto+, vesicle cycling appears to be highly dependent on mitochondrial

function. In the following sections we will review recent reports indicating how mitochondria
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can affect the distribution in pools and release properties of SAs. In particular, we reeamine

eperimental evidence which together indicate that these organelles are essential for synaptic

vesicle release under conditions of intense neuronal activity through vesicle mobilization from

the 8#. Current studies dedicated to this lin$ between mitochondria and the SA cycle will

hopefully lead to new therapeutic strategies for the handling of neurological disorders

characterized by a mitochondrial defect and which have a tremendous social impact, li$e"lzheimer%s, 2untington%s and #ar$inson%s diseases.

)ig - Schematic representation of a mitochondrial involvement in the organization ofsynaptic vesicle pools.(*+ Synaptic vesicles (SAs+ from the eo9endo cycling pool (7C#+ participate in


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neurotransmitter release at active zones (in red+. Hpon arrival of an action potential at the nerve terminal,

these vesicles fuse with the presynaptic membrane and discharge neurotransmitters in the synaptic cleft.

(-+ In contrast, SAs from the reserve pool (8#+, which contains the maority of vesicles in most synapses,

are tethered to cytos$eletal elements and are only recruited to the active zone during intense stimulation.

This recruitment of the 8# depends on "T# produced by the mitochondria. (


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Calcium 'uffering by #resynaptic &itochondriaInfluences 7o9 and 7ndocytosis of SAs

In ecitable cells, depolarization of the plasma membrane triggers the opening of

voltage9gated calcium channels, leading to Ca-B entry and a subse3uent rise of theECa-BFcytothat initiates various downstream cellular responses. In neurons, calcium

signaling is involved in neurotransmitter release from the presynaptic terminals, in

vesicle recycling via endocytosis and in long9term neuronal responses li$e neurite

growth and degeneration, or modulation of synaptic strength (Ghosh and Greenberg,

*1150 Juc$er, *1110 Konas, -?0Yao et al., -1+. Similarly to the endoplasmic

reticulum (78+, mitochondria are able to se3uester and release Ca-B ions and thereby

modulate calcium9dependent signaling events. )inally, mitochondria may also

contribute to calcium homeostasis by providing "T# to fuel the plasma membrane Ca-B9

"T#ase (Jenise$ and &atthews, -+. Considerable effort has thus been invested instudying how presynaptic mitochondria control the time9course and the amplitude of

calcium signaling.

&itochondrial calcium upta$e is driven by the negative potential established across the

inner mitochondrial membrane ()igure *+ and can be inhibited by drugs that dissipate

the proton gradient responsible for this potential (Gunter et al., -0 Graier et al.,

-6+. The outer mitochondrial membrane is relatively permeable to calcium ions, so

that Ca-B accumulation in the mitochondrial matri mainly depends on a mitochondrial

calcium uniporter (&CH+ that resides in the inner membrane ()igure *+. The &CH

shows a very low affinity for calcium ions (:m estimated between * and */1 L& in

different mitochondrial preparations+ (Gunter and Sheu, -1+, that can be overcome

by the proimity between mitochondria and the Ca-B source, i.e., the cytosolic orifice of

calcium channels at the mitochondria978 (see below+ or mitochondria9plasma

membrane contact sites, where local subdomains of high Ca-Bconcentration can be

generated (8izzuto et al., *1110 &ontero et al., -+. In heart and liver cells, an

additional calcium upta$e mechanism that does not rely on the &CH, termed rapid

upta$e mode, has also been described ('untinas et al., -*+. >nce accumulated in the

matri, calcium ions can be buffered by forming reversible Ca-B9phosphate complees, or

be eported bac$ to the cytosol by a 4aBCa-Bechanger ()igure *+ (Gunter and Sheu,

-1+. Interestingly, mitochondrial transport along microtubule trac$s is negatively

regulated by calcium (Yi et al., -=+ (see also below+, and inDrosophilaCa-Bions were

found to disrupt the interaction between the motor protein $inesin and the &iro

GT#ase, which is re3uired for the transport of these organelles along microtubules

()igure *+ (&ac"s$ill et al., -1+. Mocal subcellular regions of elevated ECa-BFcytobuilding
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up during the opening of voltage9gated plasma membrane Ca-Bchannel @ as observed

upon arrival of an action potential at the nerve terminal @ might thus cause

mitochondria to pause and transiently accumulate close to active zones where SAs will

fuse.

In neurons, ECa-BFcytopea$s stimulate SA eocytosis and hence neurotransmitter release.

This effect is mediated by synaptotagmin, a Ca-Bsensor that resides in the vesicle

membrane and promotes S4"879mediated fusion with the presynaptic membrane

(Tuc$er et al., -=0 Chic$a et al., -/+.

'y se3uestering Ca-B, presynaptic mitochondria can rapidly buffer the ECa-BFcytoand thus

diminish the SA release probability, thereby accelerating recovery of neurotransmission

after nerve stimulation. This role of mitochondria in Ca-Bbuffering is prominent in

chromaffin cells (&ontero et al., -+ and in certain types of synapses, for eample at

the rat caly of 2eld ('illups and )orsythe, --+ and at the mouse neuromuscularunction (4&K+ (avid and 'arrett, -


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hippocampal presynaptic terminals, resulting from a lac$ of the microtubule9binding

protein syntaphilin re3uired for aonal doc$ing of mitochondria ()igure *+, was shown

to cause an elevation of ECa-BFcytoduring intense stimulation, prolonging the facilitation

phenomenon observed in control neurons (:ang et al., -/+. In short, a second

conse3uence of calcium buffering by mitochondria is that neurotransmitter release canbe prolonged after the stimulus end as Ca-Bions are progressively unloaded from the

mitochondrial matri into the cytosol.

There are thus both a negative and a positive effect of mitochondrial calcium

se3uestration on synaptic activity. "ccording to the residual calcium hypothesis, a defect

in calcium buffering is epected to favor recovery from depression, as indeed observed

by several groups (ittman and 8egehr, *11/0!ang and :aczmare$, *11/+. This

however contrasts with the results from the groups of 'arrett and )orsythe discussed

above, according to which mitochondrial calcium buffering shortens synaptic depression

('illups and )orsythe, --0 avid and 'arrett, -


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promote either recovery from depression or SA depletion depending on the

eperimental conditions, and a positive effect on SA recycling.

4otably, deregulated mitochondrial Ca-Bupta$e can have deleterious conse3uences for

neurons. !hen mitochondria are overloaded with Ca-B, they undergo a dramatic event

termed mitochondrial permeability transition (T+, i.e., the formation of non9selective

pores in the inner mitochondrial membrane that allows the entry of any molecule

smaller than *,5 alton into the mitochondrial matri, causing an increase in osmotic

pressure leading to mitochondrial swelling and rupture of the outer mitochondrial

membrane (4orenberg and 8ao, -6+. Stri$ingly, synaptic mitochondria are able to

buffer less Ca-Bions and are more prone to display T than non9synaptic mitochondria

isolated from the same sample of rat cortical brain tissue ('rown et al., -?+ or mouse

sympathetic neurons (4PQez et al., -6+. The reason for this difference in Ca-B9

handling capacity remains unclear, but it might favor Ca-B9dependent eocytosis at the

presynaptic sites by maintaining a higher ECa-BFcyto. Yet a reduced Ca-B9buffering capacity

of synaptic mitochondria, caused under pathogenic conditions or by aging, may

presumably increase their susceptibility to T and subse3uent release of cell9death

molecules (see below+, leading to synapse degeneration as observed e.g., in "lzheimer%s

disease (Sel$oe, --+, schizophrenia (Glantz et al., -?+ or 2untington%s disease

(amiano et al., -*+.

In some synapses li$e e.g., theDrosophila 4&K mitochondrial contribution to

Ca-Bbuffering appears to be only minor andor easily compensated by alternative

mechanisms, at least during mild stimulation (Guo et al., -50Aerstre$en et al.,-50Mnenic$a et al., -?+. Inhibiting mitochondrial Ca-Bupta$e in fly motor nerve

terminals by adding T##B (tetraphenylphosphonium+ (Aerstre$en et al., -5+ or

antimycin "* (Mnenic$a et al., -?+ ()igure*+ does indeed not significantly influence

calcium clearance or SA mobilization and recycling after a * 2z train stimulus. In

contrast, decay of the ECa-BFcyto pea$ is significantly slowed down when the Ca-B"T#ase

mediating calcium upta$e into the 78 is pharmacologically bloc$ed or, to an even

greater etent, when the plasma membrane Ca-B"T#ase (#&C"+ is inhibited (Mnenic$a

et al., -?+. "lthough Ca-Bclearance is thus mainly ensured by the #&C" (Mnenic$a et

al., -?+, calcium storage in the 78 lumen contributes to evo$ed neurotransmitterrelease at theDrosophila4&K, supposedly by allowing the ECa-BFcytoto remain elevated

after the stimulus end (Sanyal et al., -5+. Similarly, in frog motor nerve terminals

intracellular Ca-Brelease from the 78 after cessation of stimulation leads to post9tetanic

potentiation (#T#+ (4arita et al., -+. In this contet, it is worth noting that a very

close physical connection between the 78 and mitochondria can be observed in many

cell types, including neurons (&ironov and Symonchu$, -?+. Such contacts, termed
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mitochondria9associated 78 membrane (&"&+, allow the bidirectional echange of

phospholipids and Ca-Bions between these organelles (2ayashi et al., -1b0 :ornmann

et al., -10 8izzutto et al., -1+. In mouse respiratory neurons, where both the 78

and mitochondria contribute to calcium9dependent modulation of synaptic activity,

some of the Ca-B

ions transiently accumulated within 78 vesicles in response to astimulus are subse3uently transferred to the mitochondrial matri (&ironov and

Symonchu$, -?+. If this transfer is prevented, the pea$ of ECa-BFmitoobserved after

stimulation is smaller compared to controls and neurotransmitter release is reduced

(&ironov and Symonchu$, -?+. Given the low affinity of the mitochondrial calcium

upta$e system, &"&s may thus play a critical role in the capacity of mitochondria to

promptly respond to a change in ECa-BFcytoand thereby affect many aspects of

mitochondrial biology (2ayashi et al., -1b+, including the control of SA eocytosis

andor endocytosis.

)inally, in addition to their direct effects on eocytosis and endocytosis, Ca-Bions can

also regulate the SA cycle indirectly by modulating mitochondrial bioenergetics. Three

enzymes of the :rebs cycle residing in the mitochondrial matri are indeed activated in

a calcium9dependent manner (uchen, *11-+, so that mitochondrial calcium upta$e

increases the flu of electrons through the electron transport chain (7TC+ and hence

"T# production ()igure *+ (Graier et al., -60 Gunter and Sheu, -1+. "s a

conse3uence, drugs preventing mitochondrial calcium upta$e also negatively affect "T#

production, thereby complicating the interpretation of eperimental data. Thus it is

advisable to loo$ at the effects of these drugs under conditions where the cytosolic "T#

level is artificially preserved.

In conclusion, Ca-Bions play a versatile role in several steps of the SA cycle through

different Ca-Bsensors. &itochondria thus affect eocytosis and endocytosis of SAs

through their ability to regulate Ca-Bhomeostasis. 2owever, the relative contribution of

the 78 and mitochondria to synaptic Ca-B9buffering appears to vary between different

neuronal systems and might be influenced by the integration of different signaling

pathways (8izzuto, -


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rest being provided by glycolysis in the cytosol (&athews and Aan 2olde, *115+. This

energy supply is critical since proper neuronal function re3uires "T# in order to fuel ion

pumps, to organize cytos$eletal components, to support numerous phosphorylation

reactions ("ttwell and Maughlin, -*+ and for many steps in the SA cycle including

myosin9dependent aonal transport of SAs, their S4"879mediated fusion with theplasma membrane, membrane scission, vesicle uncoating and refilling of vesicles with

neurotransmitter (&urthy and Camilli, -


14/19

"tDrosophila 4&K synapses, SAs can be assigned to different, but spatially mied

functional vesicle pools, the 7C# and 8# (:uromi and :ido$oro, -5+. Several mutants

have been used to eamine how these two vesicles pools are affected by mitochondrial

dysfunction. The first observation that was made is that synaptic communication is

rapidly inhibited when the activity of the mitochondrial "T# translocase is switched offby means of the thermosensitive mutation sesB (stress sensitive B+, suggesting that the

cytosolic pool of "T# at synaptic terminals is turned over rapidly under basal conditions

(8i$hy et al., -


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mobilization is eerted after its conversion into c" by phosphodiesterase and

adenylate cyclase. c" indeed activates the #:" $inase, which mediates unthetering

of 8# vesicles and allows their subse3uent recruitment at the active zone (:uromi and

:ido$oro, -5+. " very similar dependence of neurotransmission on mitochondrial

"T# production has recently been observed in mammalian neurons, where anterogradetransport of mitochondria along the aon relies on the adaptor protein syntabulin,

lin$ing these organelles to the $inesin heavy chain ()igure *+ (Cai et al., -5+. :noc$9

down of syntabulin or disruption of its interaction with $inesin impair neurotransmitter

release under intense stimulation conditions and this defect is partially rescued by

eogenous "T# addition (&a et al., -1+, paralleling the effects of the

fly drp1mutation (Aerstre$en et al., -5+.

Interestingly, in rat hippocampal neurons the GT#ase activity of rp* appears to be

positively regulated by the antiapoptotic protein 'cl9M(Mi et al., -/+. 'y activating

rp*, 'cl9Mpromotes mitochondrial fission and recruitment at developing synaptic

sites, and is believed to thereby increase "T# availability to fuel synaptogenesis and

further synaptic activity (Konas et al., -verepression of either

'cl9Mor rp* in rat hippocampal neurons leads to the formation of larger SA clusters

compared to controls. Conceivably, the presence of an increased number of

mitochondria at the synapses may stimulate the formation of a larger 8# andor favor

SA recycling (Mi et al., -/+. This is li$ely to be attributed to increased "T# release

from mitochondria since, at least at the s3uid giant synapse, the positive effects of 'cl9

Moverepression on neurotransmission can be mimic$ed by "T# inection (Konas et al.,

-


16/19

represent the 8# (!immer et al., -?+. In both types of calyces, this particular

distribution of mitochondria relative to synaptic vesicles might contribute to trap "T#

and glutamate @ which is generated in mitochondria from precursors emanating from

the :rebs cycle or from glutamine produced by glial cells ()igure *+ @ in restricted areas,

thereby facilitating vesicle refilling and mobilization, ensuring sustained synaptictransmission during intense neuronal activity.

In conclusion, although most processes involved in the SA cycle are $nown to be "T#9

dependent, eperimental evidence point to a critical role of mitochondrial "T#

production mostly in the establishment of large SA pools and in sustained

neurotransmitter release during intense neuronal activity, i.e., for mobilization of 8#

vesicles and for vesicle recycling via endocytosis. In contrast, low "T# levels produced

by glycolysis in the cytosol appear to be sufficient to fuel other steps of the SA cycle

(Calupca et al., -*+, and this is li$ely accomplished by optimal positioning of

glycolytic enzymes close to the "T# consumption sites

&itochondria and isease

"s described above, energy generation by mitochondria is of maor importance for the

SA cycle in neurons, and one can epect that disturbed "T# production may have

deleterious conse3uences for neurons in health and disease. efects in most of the

complees of the 7TC ()igure *+ are indeed associated with different neurodegenerativediseases and numerous mutations in mitochondrial9associated proteins have been

lin$ed to a variety of neurological diseases (My and Aerstre$en, -?+.

>ne of the best $nown eamples of this is #ar$insonism. The first evidence that

mitochondria are involved in #ar$inson%s disease (#+ came from the observation that

mitochondrial drugs li$e T# and rotenone that specifically affect comple I of the

7TC ()igure *+ cause #9li$e symptoms, including degeneration of dopaminergic

neurons (German et al., *1/10 'etarbet et al., -0#anov et al., -5+. It was later

shown that mutations in the #ar$inson related genepink1similarly lead to a reduced

comple I activity (Gautier et al., -/0 &orais et al., -1+. The product of two other

#ar$inson related genes,parkinandDJ-1, also appear to be involved in the regulation of

mitochondrial functions ('onifati et al., -


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"side from direct 7TC dysfunction that leads to reduced "T# production, disturbed

mitochondrial transport to sites of high energy demand, including synapses, may also

lead to local "T# depletion and thus synaptic transmission deficits. "s discussed before,

8#*, a regulator of mitochondrial fission appears to be a $ey regulatory switch

controlling mitochondrial transport and thus synaptic "T# production, possibly inresponse to calcium influ and neuronal activity (Mee et al., -=0Aerstre$en et al.,

-50Cereghetti et al., -/+. !hile to date no inherited disease resulting directly from

mutations in genes regulating fission are $nown0 increased levels of 8#*, and thus

presumably also increased mitochondrial fission and synaptic transport has been

implicated in alleviating #ar$inson disease9li$e phenotypes in flies, yet it is still unclear

whether these effects are direct or not (&orais et al., -10#oole et al., -*+. Indeed,

increased 8#* activity is predicted to augment synaptic "T# production by

concentrating mitochondria at active synapses, in turn facilitating SA mobilization.

The converse process, mitochondrial fusion, results in lower mitochondrial membrane

potential and thus reduced "T# production (Chen and Chan, -5+ and is associated

with neurodegeneration. Three proteins are re3uired for mitochondrial fusion >#"*,

mitofusin * (&fn*+ and mitofusin - (&fn-+ (Chen and Chan, -5+. The latter two

proteins are also re3uired for aonal transport of mitochondria (&is$o et al., -*+.

&)4- has been identified as one of the genes causing Charcot9&arie9Tooth type -"

(C&T-"+ syndrome. C&T-" is a neuropathy that affects sensory and motor neurons of

the distal etremities and is characterized by progressive wea$ness of the muscles

followed by muscular atrophy (Juchner et al., -=+. &utations in >#"* cause

autosomal dominant optic atrophy (>"+, characterized by a degeneration of retinalganglia cells leading to optic nerve atrophy ("leander et al., -0elettre et al.,

-+. "t first sight it might seem that mutations in two genes encoding proteins

involved in mitochondrial fusion cause two diseases with differential phenotypes. Yet

C&T-" patients have been described to suffer from optic atrophy ('anchs et al., -/+.

Mi$ewise, some >" patients epress additional symptoms including peripheral motor9

sensory neuropathy ("mati9'onneau et al., -/+. Min$ing these mitochondrial fusion

related diseases to defects in neuronal function, the reduced "T# levels as a

conse3uence of less mitochondrial fusion may be responsible for defects in SA release

andor recycling under intense stimulation. Ta$en together, these data support thehypothesis that "T# production may play a critical role in neuronal communication

during intense stimulation and that mitochondria play a specific role in regulating

synaptic strength, suggesting that neurological disorders with defects in presynaptic

mitochondrial function or mitochondrial transport also display abnormalities in the SA

cycle.
http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B71http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B112http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B112http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B24http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B24http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B82http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B95http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B95http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B26http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B26http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B80http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B124http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B1http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B34http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B34http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B34http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B7http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B3http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B71http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B112http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B112http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B24http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B82http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B95http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B26http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B26http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B80http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B124http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B1http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B34http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B34http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B7http://journal.frontiersin.org/Journal/10.3389/fnsyn.2010.00139/full#B3


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>ne puzzling feature common to all the diseases discussed here is the selective tissue

vulnerability associated with mitochondrial defects. )irst of all, the particular mode of

mitochondrial inheritance might contribute to the appearance of clinical manifestations

only in a specific cell population, since stochastic distribution of mitochondria between

daughter cells can lead to very different ratio of mutant to wild9type organelles aftercyto$inesis (Chan, -?+. Such a genetic drift has indeed been observed for some

mitochondrial encephalomyopathies where mitochondrial 4" carrying the causative

mutation accumulates in a specific region of the brain (:urenai et al., -0 'etts et al.,

-?+, although the underlying mechanisms remains un$nown.

&oreover, compared to other cell types neurons appear particularly susceptible to

mitochondrial dysfunction. This is most li$ely related to their very high energy demands

and their specific architecture, as mitochondria must travel long distances from the cell

body to reach regions of intense "T# consumption li$e the presynaptic sites. efective

mitochondrial fusion andor fission @ and hence altered mitochondria recruitment at

the nerve terminals @ is thus particularly detrimental for these cells (Guo et al.,

-50Aerstre$en et al., -5+. This is epected to be even more critical for neurons

possessing a very long aon, li$e those innervating distal muscles that are affected in

patients with C&T disease (&is$o et al., -*+.

)inally, in addition to this cellular contet the tissue contet might also influence the

sensitivity of some neurons to mitochondrial dysfunction. )or eample, dopaminergic

neurons which are progressively lost in # are innervated by glutamatergic neurons,

li$ely ma$ing them more susceptible to glutamate ecitotoicity and hence to calciumoverload (Caudle and Jhang, -1+. " defect in mitochondrial calcium handling

capacity andor bioenergetics would in this model predispose dopaminergic neurons to

ecitotoic damage and be particularly detrimental for them compared to other cell

types (Greene and Greenamyre, *11?0 4icholls et al., -6+. !e thus surmise that

dysfunction or degeneration of specific neuronal populations in specific neurological

diseases may be a conse3uence of both cell autonomous effects that inherently regulate

mitochondrial function and cell non9autonomous effects, where the particular cellular

contet a neuron finds itself in may (over9+ stress mitochondrial function.

In conclusion, there is now accumulating evidence that the capacity of presynaptic

mitochondria to produce "T# and to buffer Ca-Bis of maor importance to maintain

neuronal communication, at least in part by controlling SAs mobilization and recycling.

&itochondrial dysfunctions lin$ed to neurodegenerative diseases are thus li$ely to eert

their effect at least in part through an alteration of the SA cycle. In the light of the

literature detailed above, it seems reasonable to speculate that disease9related
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mutations that eventually cause a reduction of mitochondrial "T# production and

calcium buffering capacity in the nerve terminals would negatively affect

neurotransmission by preventing replenishment of the 7C# and vesicle mobilization

from the 8#, as indeed observed in pin$* mutantDrosophilawhere epression of a

clinical mutant fails to rescue 8# mobilization.

malate aspartate shuttle

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