The Parkinson Disease Mitochondrial Hypothesis: Where Are We At?
The Parkinson Disease Mitochondrial Hypothesis: Where Are We At?
The Parkinson Disease Mitochondrial Hypothesis: Where Are We At?
research-article2015
NROXXX10.1177/1073858415574600The NeuroscientistFranco-Iborra et al.
Review
The Neuroscientist
Abstract
Parkinsons disease is a common, adult-onset neurodegenerative disorder whose pathogenesis is still under intense
investigation. Substantial evidence from postmortem human brain tissue, genetic- and toxin-induced animal and cellular
models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of the disease. This review
discusses our current understanding of Parkinsons diseaserelated mitochondrial dysfunction, including bioenergetic
defects, mitochondrial DNA alterations, altered mitochondrial dynamics, activation of mitochondrial-dependent
programmed cell death, and perturbations in mitochondrial tethering to the endoplasmic reticulum. Whether a
primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the
progression of neurodegeneration in Parkinsons disease.
Keywords
complex I, apoptosis, fusion/fission, mtDNA, mitochondria-associated endoplasmic reticulum membranes
phosphorylation. This hypothesis was supported by the between complex I inhibition and sporadic PD was estab-
discovery of DNA in mitochondria and by the fact that lished when several groups reported reduced complex I
mitochondria were found to have their own machinery for activity in the brains of patients with PD (Hattori and oth-
protein synthesis. The primary function of mitochondria is ers 1991; Schapira and others 1990). It was also demon-
the generation of cellular energy in the form of adenosine strated that catalytic subunits of complex I derived from
5-triphosphate (ATP) by oxidative phosphorylation. As PD frontal cortex mitochondria are oxidatively damaged,
such, mitochondria are usually considered the power- correlating with complex I misassembly and dysfunction
houses of the cell. However, mitochondrial biological (Keeney and others 2006). However, diminished activity
function extends well beyond just the production of in complex I has not only been reported in the postmortem
energy; they are highly dynamic organelles with complex substantia nigra but also seems to extend to multiple neu-
structural features that have important cellular functions ronal and non-neuronal regions, including the cortex, skel-
such as the metabolism of amino acids and lipids, as well etal muscles, fibroblasts and platelets of PD patients
as housing intermediate metabolic pathways such as pyru- (Parker and others 1989; Schapira and others 1990). Thus,
vate oxidation, the Krebs cycle, the regulation of calcium the relevance of complex I inhibition to disease pathogen-
homeostasis, free radical scavenging or the control of pro- esis remains uncertain and several key questions remain to
grammed cell death (PCD). be explained: (a) How does a systemic defect cause selec-
Cells contain many mitochondria, each of which car- tive degeneration of the dopamine neurons of the substan-
ries several copies of a small circular mitochondrial tia nigra pars compacta? (b) Knowing that complex I
genome in the matrix. While it was thought that the mito- activity should be reduced by more than 50% to cause sig-
chondrion was a rigid organelle, it is now clear that mito- nificant ATP depletion in non-synaptic brain mitochondria
chondria undergo constant morphological changes due to (Davey and Clark 1996), why is it that a reduction of only
repetitive cycles of fusion (the combination of two mito- 25% to 30% of complex I activity in PD patients (Schapira
chondria into a single organelle) and fission (the separa- and others 1990) might play a major role in energy failure
tion of long, tubular mitochondria into two or more in PD-related dopaminergic neurodegeneration? (c) Does a
smaller parts), resulting in a wide range of mitochondrial deficit in complex I represent a primary or secondary event
morphologies. This phenomenon is regulated by a deli- in the pathogenesis of PD?
cate balance between these two opposing processes; in Our own view is that the complex I defects are likely
turn, the balance influences most mitochondrial functions to be critical in the pathogenesis of dopaminergic neuro-
and allows mitochondrial integrity, bioenergetic function, nal loss, probably in combination with other defects
mitochondrial turnover, and protection of mtDNA to be (Fig. 1). Indeed, we showed that structural alterations to
maintained. complex I linked to a deficiency in apoptosis-inducing
factor (AIF) do not cause dopaminergic neurodegenera-
Do Alterations to Mitochondrial tion per se, but increase the susceptibility of dopaminer-
Respiration Participate in PD gic neurons to exogenous parkinsonian neurotoxins
(Perier and others 2010). However, it still remains to be
Neurodegeneration? elucidated if the majority of PD patients or only a portion
Over the past 25 years, publications in the field of of them present a complex I deficiency.
PD-related mitochondrial dysfunction have increased Nonetheless, even if energy failure might not be
exponentially in number and many studies have demon- responsible for DA cell death, it is now clear that mito-
strated that alterations in mitochondrial function are cen- chondrial dysfunction induces the chronic production of
tral to the pathogenesis of PD. reactive oxygen species (ROS) and is instrumental in
Several lines of evidence sustain a link between spo- the demise of DA neurons. ROS include the superoxide
radic PD and a dysfunctional respiratory chain, in particu- anion (O2-), hydrogen peroxide (H2O2), and the
lar a deficit in complex I activity. In 1983, Langston and hydroxyl radical (OH). H2O2 and OH are potent oxi-
others observed that accidental exposure of drug abusers to dants that extract electrons from other molecules such
1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an as DNA, proteins and lipids, thereby altering their prop-
inhibitor of complex I (NADH/ubiquinone oxidoreduc- erties. Complex I is known to be the major source of
tase) of the mitochondrial electron transport chain, resulted superoxide production in the electron transport chain in
in an acute and irreversible parkinsonian syndrome that presence or absence of toxins. Oxidative damage to pro-
was almost indistinguishable from PD. In 2000, the group teins, lipids and DNA has been observed in postmortem
led by Greenamyre reported that the chronic, systemic brain samples from PD patients (Dauer and Przedborski
inhibition of complex I by the pesticide rotenone, causes 2003), while the PD-linked protein DJ-1, mutations of
highly selective nigrostriatal dopaminergic degeneration which cause an autosomal recessive form of PD
(Betarbet and others 2000). Finally, a biochemical link (Bonifati and others 2003), has been identified as a
268 The Neuroscientist 22(3)
apoptosis in vitro (Iaccarino and others 2007). On the death role in experimental in vivo models of PD remains
other hand, wild-type DJ-1 protects cells from apoptosis to be demonstrated, as mutant mice partially deficient for
(Venderova and Park 2012), whereas DJ-1 deficiency AIF are not only not protected against MPTP intoxication
increases oxidative stress-induced apoptotic cell death but are also much more sensitive to the deleterious effects
(Martinat and others 2004). Overexpression of wild-type of this parkinsonian neurotoxin (Perier and others 2010).
PINK1, but not of PD-associated PINK1 mutants, is able
to attenuate cytochrome c release (Wang and others Alterations to Mitophagy, an Emerging
2007). Parkin prevents cytochrome c release (Darios and Problem for PD
others 2003) and apoptosis by the inhibition of Bax trans-
location (Charan and others 2014), while the overexpres- Autophagy is a process whereby the cytoplasmic contents
sion of -synuclein is associated with complex I inhibition of a cell are sequestered within double membrane vacu-
(Loeb and others 2010) (Fig. 4). A recent study showed oles, called autophagosomes (AP), and subsequently
that human -synuclein in yeast cells also triggers mito- delivered to the lysosome for degradation. There are at
chondria-nuclear translocation of EndoG and EndoG- least two ways in which alterations of autophagic path-
mediated DNA degradation (Bttner and others 2013), ways may participate in the demise of dopaminergic neu-
indicating that -synuclein toxicity may activate apopto- rons. First, when the autophagic processes are insufficient
sis as well as caspase-independent cell death. to remove the accumulation of protein aggregates, such
Among the caspase-independent programmed cell as -synuclein. Second, the up-regulation of autophagy is
death scenarios, necrosis, which has traditionally been considered to be a direct contributor to cell death.
considered as passive cell death, is now considered a Increased numbers of AP have been observed in cultured
genetically programmed pathway with necrotic morphol- cells exposed to parkinsonian neurotoxins such as MPP+,
ogy. Programmed necrosis (or necroptosis) is associated rotenone and 6-OHDA (Dehay and others 2013), and in
with a rapid bioenergetic failure, ROS formation, and loss postmortem PD brain samples (Anglade 1997). However,
of plasma membrane integrity. Relatively few studies controversy exists as to whether autophagy promotes or
have been performed to study the involvement of pro- prevents cell death. If autophagy removes damaged mito-
grammed necrosis in the pathogenesis of PD, as for a long chondria that would otherwise activate caspases and
time, studying PCD in PD was synonymous with search- apoptosis, then autophagy should be protective. However,
ing for apoptotic cells in post mortem tissue and in models excessive and dysregulated autophagy may promote cell
of the disease. Nonetheless, recent evidence suggests its death, since enzymes leaking from lysosomes, such as
implication, and in particular the involvement of exces- cathepsins, can initiate mitochondrial permeabilization,
sive activation of poly(ADP-ribose) polymerase-1 (PARP- caspase activation and apoptosis. In 2005, the term
1), which gives rise to a caspase-independent form of mitophagy for the selective autophagy of mitochondria
PCD, termed parthanatos.. PARP-1 activation is an was proposed (Lemasters 2005), and in recent years the
early biochemical cell death event that is to a large extent link between mitophagy and PD has emerged as a new
mediated by the accumulation of poly (ADP-ribose) pathogenic hypothesis in PD. As reviewed elsewhere
(PAR) and nuclear translocation of AIF from the mito- (Vives-Bauza and Przedborski 2011; Youle and Narendra
chondria. The activation of PARP-1 contributes to MPTP- 2011), the loss of mitochondrial membrane potential,
induced dopaminergic neurodegeneration (Wang and which often correlates with dysfunctional mitochondria,
others 2009), as demonstrated by PARP/ mice, which seems to be a common signal for the mitochondria to be
are resistant to MPTP intoxication (Mandir and others cleared via mitophagy. In mammalian cells, Parkin is
1999). This finding led the team of Dawson to propose recruited to depolarized mitochondria, which are subse-
that excessive activation of PARP-1 leads to parthanatos, quently eliminated by autophagy. Parkin translocation to
in which PAR polymer appears to be a pro-death signaling mitochondria relies on PINK1 expression, suggesting
molecule that acts as a nuclear-mitochondrial signal to that PINK1 is a key signaling molecule in mitophagy.
release AIF from the mitochondria in PARP-1-dependent Loss of DJ-1 leads to impaired autophagy, the accumula-
cell death (Andrabi and others 2008) (Fig. 4). Although tion of dysfunctional mitochondria (Krebiehl and others
PAR polymer involvement was not demonstrated in the 2010), and a fragmented mitochondrial phenotype
context of the pathogenesis of PD, in vitro experiments (Irrcher and others 2010). Interestingly, PINK1 and
have shown that AIF can be released from the mitochon- Parkin can rescue the mitochondrial fragmentation
dria, along with cytochrome c, following complex I inhi- induced by the loss of DJ-1 (Irrcher and others 2010).
bition with MPP+, the active metabolite of MPTP (Chu These findings suggest that the different PD-related pro-
and others 2005). Furthermore, small interfering RNA- teins linked to the mitochondria contribute to the patho-
mediated knockdown of AIF in dopaminergic cell lines is genesis of the disease at the intersection of mitochondrial
able to delay MPP+-induced cell death (Chu and others dysfunction and autophagy (Fig. 4). However, to date,
2005). However, whether AIF plays an actual pro-cell questions remain to be addressed: the majority of the
272 The Neuroscientist 22(3)
Figure 4. Activation of mitochondrial-dependent programmed cell death pathways in Parkinsons disease (PD). (A) Apoptosis
can be activated following complex I inhibition, which gives rise to reactive oxygen species (ROS) production and the activation
of intrinsic pro-apoptotic pathways (broken arrow; for more details see Perier and others 2012), which facilitate mitochondrial
Bax translocation and release of cytochrome c (cyt c) into the cytosol. Mitochondrial PINK1 can attenuate cytochrome c
release and apoptotic cell death by phosphorylating HTRA2 (high temperature requirement A2) or TRAP1 (tumor necrosis
factor receptor-associated protein 1), two of its putative substrates. Mitochondrial Parkin, in turn, can prevent mitochondrial
swelling, cytochrome c release, and apoptotic cell death. In addition, Parkin also regulates mitochondrial biogenesis through its
interaction with the mitochondrial transcription factor A (TFAM). -Synuclein (-syn) has been shown to directly interact with
mitochondria, where it can have a deleterious role by inhibiting complex I, increasing the production of ROS, and promoting
the release of cytochrome c. LRRK2 (leucine-rich-repeat kinase 2) is partly localized to the mitochondria, where it can induce
the release of cyt c and subsequent apoptotic cell death. (B) Necrosis can simultaneously occur with apoptosis. PARP-1 is
activated in response to ROS-induced DNA damage, which results in excessive production of PAR polymers, a major product
of PARP-1 activation, and NAD+ and ATP depletion. Such activation acts as a pro-death signal for the mitochondrion-to-
nucleus translocation of AIF, which causes DNA fragmentation and programmed cell death. Mitochondrial outer membrane
permeabilization represents the point-of-no-return in the mitochondrial apoptotic pathway, since once released into the cytosol,
mitochondrial factors can initiate cell death in a caspase-dependent or a caspase-independent manner. (C) Mitophagy, the
selective autophagic degradation of dysfunctional mitochondria, can be disrupted by PD-causing mutations in PINK1 and Parkin,
thus resulting in the accumulation of undegraded, dysfunctional mitochondria that can cause cell dysfunction and ultimately cell
death. Dashed arrows show unresolved pathways. Broken arrow represents described pathways.
studies performed to understand the mitophagic function Mitochondria and Their Close Neighbor, the
of Parkin were performed in Parkin-overexpressing cells; Endoplasmic Reticulum
at endogenous levels, Parkin fails to mediate mitophagy
in human primary fibroblasts and in induced pluripotent Mitochondria do not exist in isolation but interact physi-
stem cell-derived neurons (Rakovic and others 2013), cally with many other subcellular organelles in a coopera-
thus questioning the physiological relevance of this path- tive manner to facilitate rapid and efficient signaling and
way in the mammalian brain in the presence of endoge- metabolism. An example of such is their interaction with
nous levels of PINK1/Parkin. the endoplasmic reticulum (ER), first reported by
Franco-Iborra et al. 273
morphological data using electron microscopy (Bernhard site where classical processes tied to neurodegeneration
and Rouiller 1956). Mitochondria-associated ER mem- take place. In fact, proteins such as Drp1 or MFN2, which
branes, or MAM, display a particular sedimentation pro- are linked to neurodegenerative diseases, are enriched in
file, composition and enzymatic activity that are different MAM (de Brito and Scorrano 2008). When taken together,
from the bulk ER (Vance 2014). They are enriched in activ- one might wonder whether ER-mitochondrial contacts
ities related to lipid metabolism, particularly in relation to might contribute to the pathogenesis of neurodegenerative
cholesterol and phospholipid synthesis enzymes and cal- diseases.
cium-handling proteins. Nonetheless, ERmitochondrial In the case of PD, it has been reported that -synuclein is
contacts are much more than a simple approximation present not only in the cytosol but is also associated with
between the two organelles. In effect, they are tethered the mitochondria (Stefanis 2012) and that overexpression
through different protein interactions, which are reversible of -synuclein leads to an increase of calcium transfer from
and regulated, as evidenced by the interaction between the ER to the mitochondria, together with an up-regulation
VDAC (voltage-dependent anion-selective channel) and of mitochondriaER contacts in human cells. In contrast, a
IP3 receptor (Szabadkai and others 2006) or by the enrich- siRNA-mediated down-regulation of -synuclein reduces
ment of Mitofusin 2 (MFN2) at the ER-mitochondrion mitochondrial-calcium uptake (Cal and others 2012). More
interface. Mitofusin 2 not only participates in mitochon- recently, it was shown that -synuclein is also localized at
drial fusion but also interacts with MFN1 or MFN2, pres- the MAM (Guardia-Laguarta and others 2014), where it
ent on the mitochondrial surface, leading to the promotes the transfer of calcium from the ER to the mito-
aproximation of both organelles (de Brito and Scorrano chondria (Cal and others 2012). Remarkably, PD-linked
2008). The close apposition between mitochondria and -synuclein mutations disrupt the association of -synuclein
ER, together with the selective presence of proteins and with MAM, resulting in a decreased apposition of ER with
enzymes in this region, makes the ERmitochondrial sur- the mitochondria and a decrease in MAM function
face the perfect site for key cellular processes such as lipid (Guardia-Laguarta and others 2014). Furthermore, DJ-1
transfer and metabolism, calcium transfer/signaling and modulates mitochondrial calcium levels by favoring
cell death, to take place (Fig. 5). The accumulation of cal- ER-mitochondria tethering. A reduction of DJ-1 levels
cium within mitochondria leads to the activation of oxida- results in mitochondria fragmentation and decreased mito-
tive phosphorylation by regulating the activity of three chondrial calcium uptake in stimulated cells, suggesting
dehydrogenases in the Krebs cycle (Denton 2009); this is that the impairment of ER-mitochondrial communication,
crucial for matching ATP production to metabolic demands as a consequence of DJ-1 loss-of-function, may play a role
stemming from neuronal electrical activity. SNpc dopami- in the mitochondrial dysfunction observed in PD (Ottolini
nergic neurons are autonomously active, with the pace- and others 2013) (Fig. 5).
making activity of these neurons driven by
voltage-dependent L-type calcium channels, leading to Conclusions: From Mitochondrial
sustained elevations in cytosolic calcium concentrations
(Chan and others 2007). The large calcium-buffering bur-
Dysfunction to Neuroprotection
den created by pacemaking activity in SNpc dopaminergic As mitochondria are central to the regulation of energy
neurons ultimately compromises mitochondrial function production, calcium homeostasis, bioenergetic quality
which may thus underlie the selective vulnerability of control and cell death regulation, maintaining their func-
SNpc dopaminergic neurons in PD. Indeed, as reviewed tions in an operational manner is thus a priority for the cell.
elsewhere (Rao and others 2014), calcium overload in the This dependence of cells on the mitochondrial energy pro-
mitochondria favors the opening of the mitochondrial per- duction is particularly true for dopaminergic neurons of the
meability transition pore (PTP), together with cytochrome SNpc as in humans the brain uses more energy than any
c release and apoptosis. Szalai and others (1999) showed other organ (~20% of the bodys total demand), and those
that IP3 receptorinduced opening of the PTP is dependent neurons have as a common characteristic to be long-range
on calcium signal transmission from IP3 receptors to the projection neurons with an elaborate axonal arborisation
mitochondria. Inside the mitochondria, calcium binds to and a high rate of mitochondrial oxidative metabolism. It is
adenine-nucleotide-translocator, which is thought to be now well established that mitochondrial dysregulation
converted into an unselective channel. This leads to the plays a central pathogenic role in PD. However, to date,
swelling of the inner mitochondrial membrane together there is no clear indication as to whether mitochondrial
with the loss of membrane potential. Another consequence dysfunction is a cause of PD or instead is correlated with
is the breakdown of the outer mitochondrial membrane the progression of the disease. If mitochondrial dysfunc-
and, finally, the release of pro-apoptotic factors such as tion is central to the pathogenesis of PD, one could expect
cytochrome c. This is only one example of how this newly to see PD symptoms in patients with mitochondrial disor-
identified subdomain in the ER/mitochondria may be the ders. Reeve and others (2013) recently analyzed the effects
274 The Neuroscientist 22(3)
Figure 5. Endoplasmic reticulum (ER)mitochondrial contacts and Parkinsons disease (PD). The ERmitochondrial junction
is the site where key cellular processes take place. The close apposition between ER and mitochondrial proteins enables the
formation of an apoptosis platform in the BAP31-Fis1 interaction. This mediates pro-caspase-8 recruitment and activation, leading
to generation of the p20Bap31 apoptotic fragment that activates calcium release from ER stores. Calcium release from inositol-
1,4,5-triphosphate receptor 3 (IP3R3) is facilitated because of its interaction with voltage-dependent anionic channels (VDAC)
through the molecular chaperone grp75. Another ER-mitochondrial tether is Mitofusin 2 (MFN2), which is also located in
mitochondria-associated ER membranes (MAM) and can interact with Mitofusin 1 (MFN1) and MFN2 in the outer mitochondrial
membrane. ER-mitochondrial contacts play an important role in the pathogenesis of PD. -Synuclein (-syn) overexpression
leads to increased calcium transfer due to the up-regulation of ERmitochondrial contacts, which can result in calcium-dependent
apoptosis. Whereas -syn has been shown to localize to MAM, PD-linked mutations in -syn disrupt this association, thus
decreasing ERmitochondrial apposition. On the other hand, DJ-1 favors ER-mitochondrial tethering, with reduced DJ-1 levels
resulting in decreased mitochondrial calcium uptake. Ca2+ = calcium; MCU = mitochondrial calcium uniporter; PTP = permeability
transition pore.
of mitochondrial mutationsknown to cause cell loss and Different therapeutic strategies were proposed to
dysfunction in other brain regions and tissueson mito- bypass mitochondrial dysfunctions in experimental PD.
chondrial function and dopaminergic neurons in patients. These include the boost of energy production, the scav-
Defects in both complex I and complex IV of the respira- enging of free radicals, the inhibition of calcium entry
tory chain were seen in SNpc neuron mitochondria, but within the cell, the inhibition of mitochondria-dependent
only a subset of patients with mutations in POLG exhibited PCD, and the inhibition of mitochondrial division.
marked neuronal loss. Why are only a few cases of mito- Unfortunately, so far, none of those treatment strategies
chondrial disease associated with Parkinsonism? Two have provided an ameliorative effect on motor symptoms
hypothesis can be advanced: (a) Neurons in which a defect in patients. Disappointing clinical trial results involving
develops early in life are more able to adapt and less likely mitochondrial therapies have raised the question of
to degenerate and (b) as dopaminergic cell loss was only whether the presently used animal models adequately
observed in some mitochondrial patients with POLG muta- reflect the underlying neurodegenerative processes of
tions associated with -synuclein pathology (Reeve and idiopathic PD. We strongly believe that even if the exist-
others 2013), it is possible that mitochondrial dysfunction ing models are far from being ideal, and the development
below a given threshold is not sufficient to induce dopami- of new animal models is necessary, the classical toxin-
nergic cell death but may be part of a more complex multi- based animal models have greatly contributed to the
factorial pathogenic process. development of current PD treatments such as l-dopa,
Franco-Iborra et al. 275
dopamine agonists, and monoamine oxidase-B inhibitors, Bernhard W, Rouiller C. 1956. Close topographical relation-
and have increased our understanding of the basal ganglia ship between mitochondria and ergastoplasm of liver cells
circuitry, pathogenic mechanisms, and potential thera- in a definite phase of cellular activity. J Biophys Biochem
peutic targets for PD. The actual challenge will be to Cytol 2:738.
Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS,
refine the process of patient selection into clinical trials
and others. 2014. Loss of mitochondrial fission depletes
and to develop early clinical markers for PD. Indeed, it is
axonal mitochondria in midbrain dopamine neurons. J
likely that a number of factors participate in the patho- Neurosci 34:1430417.
genesis of the disease and it might be necessary to iden- Betarbet R, Sherer TB, Mackenzie G, Garcia-Osuna M, Panov
tify subgroups of patients that may potentially benefit AV, Greenamyre JT. 2000. Chronic systemic pesticide
from candidate drugs affecting mitochondrial function exposure reproduces features of Parkinsons disease. Nat
(patients with decreased complex I activity, patients with Neurosci 3:13016.
Parkin/PINK1 mutations, etc.). Furthermore, by the time Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ,
most patients develop the typical clinical symptoms of Krieger E, and others. 2003. Mutations in the DJ-1 gene
PD, it is estimated that at least 60% of nigral dopamine associated with autosomal recessive early-onset parkinson-
neurons have degenerated. For a potential neuroprotec- ism. Science 299:2569.
Bttner S, Habernig L, Broeskamp F, Ruli D, Vgtle FN,
tive agent to be most effective, patients need to be treated
Vlachos M, and others. 2013. Endonuclease G medi-
early, and before significant cell loss has occurred. For
ates -synuclein cytotoxicity during Parkinsons disease.
this it is necessary for early clinical markers for PD to be EMBO J 32:304154.
developed. Despite the challenges lying ahead, we are Cal T, Ottolini D, Negro A, Brini M. 2012. -Synuclein con-
confident that in the next few years, major breakthroughs trols mitochondrial calcium homeostasis by enhancing
relating to mitochondrial therapies will appear. endoplasmic reticulummitochondria interactions. J Biol
Chem 287:1791429.
Declaration of Conflicting Interests Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch
The author(s) declared no potential conflicts of interest with T, and others. 2007. Rejuvenation protects neurons in
respect to the research, authorship, and/or publication of this mouse models of Parkinsons disease. Nature 447:10816.
article. Chang DTW, Honick AS, Reynolds IJ. 2006. Mitochondrial
trafficking to synapses in cultured primary cortical neu-
rons. J Neurosci 26:703545.
Funding Charan RA, Johnson BN, Zaganelli S, Nardozzi JD, LaVoie
The author(s) disclosed receipt of the following financial sup- MJ. 2014. Inhibition of apoptotic Bax translocation to the
port for the research, authorship, and/or publication of this arti- mitochondria is a central function of parkin. Cell Death Dis
cle: This work was supported by the Fondo de Investigacin 5:e1313.
Sanitaria, Instituto de Salud Carlos III (FIS-ISCIII, Spain), Chu CT, Zhu J, Cao G, Signore A, Wang S, Chen J. 2005.
Ministerio de Ciencia e Innovacin (MICINN, Spain), Fundaci Apoptosis inducing factor mediates caspase-independent
Marat de TV3 (Spain) and Centro de Investigacin Biomdica 1-methyl-4-phenylpyridinium toxicity in dopaminergic
en Red en Enfermedades Neurodegenerativas (CIBERNED, cells. J Neurochem 94:168595.
Instituto de Salud Carlos III, Spain). CP is supported by the Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider BL.
Ramn y Cajal Program from MICINN (Spain). SF-I is sup- 2012. Sustained expression of PGC-1 in the rat nigrostria-
ported by the Formacin de Profesorado Universitario Program tal system selectively impairs dopaminergic function. Hum
(FPU13/01339) from Ministerio de educacin, cultura y deporte Mol Genet 21:186176.
(FPU, Spain). Dai Y, Clark J, Zheng K, Kujoth GC, Prolla TA, Simon DK.
2014. Somatic mitochondrial DNA mutations do not
increase neuronal vulnerability to MPTP in young POLG
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