Journal of Cell Death

Review

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Dysfunctional Mitochondrial Dynamics in the Pathophysiology

of Neurodegenerative Diseases
Florian Haun14, Tomohiro Nakamura1 and Stuart A. Lipton1
Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical
Research Institute, La Jolla, CA. 2Institute of Molecular Medicine and Cell Research; 3Spemann Graduate
School of Biology and Medicine; 4Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
Corresponding author email: slipton@sanfordburnham.org
1

Abstract: Mitochondrial dysfunction occurs in neurodegenerative diseases, however molecular mechanisms underlying this process
remain elusive. Emerging evidence suggests that nitrosative stress, mediated by reactive nitrogen species (RNS), may play a role in
mitochondrial pathology. Here, we review findings that highlight the abnormal mitochondrial morphology observed in many neurodegenerative disorders including Alzheimers, Parkinsons, and Huntingtons diseases. One mechanism whereby RNS can affect mitochondrial function and thus neuronal survival occurs via protein S-nitrosylation, representing chemical reaction of a nitric oxide (NO)
group with a critical cysteine thiol. In this review, we focus on the signaling pathway whereby S-nitrosylation of the mitochondrial
fission protein Drp1 (dynamin-related protein 1; forming S-nitrosothiol (SNO)-Drp1) precipitates excessive mitochondrial fission or
fragmentation and consequent bioenergetic compromise. Subsequently, the formation of SNO-Drp1 leads to synaptic damage and neuronal death. Thus, intervention in the SNO-Drp1 pathway may provide therapeutic benefit in neurodegenerative diseases.
Keywords: S-nitrosothiol, neurodegeneration, dendritic spine loss, GTPase, reactive nitrogen species, mitochondrial dysfunction

Journal of Cell Death 2013:6 2735

doi: 10.4137/JCD.S10847
This article is available from http://www.la-press.com.
the author(s), publisher and licensee Libertas Academica Ltd.
This is an open access article published under the Creative Commons CC-BY-NC 3.0 license.
Journal of Cell Death 2013:6

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Haun et al

Introduction

Mitochondria are dynamic organelles capable of

establishing interconnected networks. Dynamic morphological changes are mediated by continual, highlyregulated fusion and fission events, collectively
termed mitochondrial dynamics.1 For example, the
evolutionarily conserved GTPase, dynamin related
protein1 (Drp1), is known to participate in the process of mitochondrial fission.1 When mitochondria
undergo fission, cytosolic Drp1 translocates to the
outer mitochondrial membrane, oligomerizes around
mitochondrial tubules, and in conjunction with Fis1
promotes division or fission.1 The fusion machinery
consists mainly of three additional large dynaminlike GTPases: both mitofusin1/2 (Mfn1/2) and optic
atrophy protein 1 (Opa1).2 The strict regulation of
the equilibrium between fusion and fission events

governs mitochondrial dynamics in a healthy cell

and is crucial to maintaining mitochondrial function affecting energy supply, response to apoptotic
stimuli, mitochondrial inheritance via admixture of
mitochondrial-DNA (mtDNA), and translocation of
mitochondria to regions of high-energy demand.3
Although mitochondrial dynamics are crucial in all
cell types, neurons are thought to be especially dependent on a dynamic mitochondrial network.4 With their
often long processes, neurons require proper distribution of mitochondria across long distances to satisfy
the energy requirements of electrical excitability and
synaptic transmission (Fig. 1). To this end, healthy
neurons precisely control mitochondrial dynamics in
order to efficiently transport mitochondria to distal
locations, including dendrites, axons, and synapses.3
Thus, mitochondrial function is essential to many

Figure 1. Proposed model of excessive mitochondrial fission contributing to neurodegenerative disorders. Balanced mitochondrial dynamics (mitochondrial fission and fusion events) facilitate proper distribution of neuronal mitochondria within neuronal dendrites and into synaptic termini. In addition, the
precise control of mitochondrial fission and fusion events in axons is needed to support normal neuronal function (e.g., via production of ATP and buffering
of Ca2+). Malfunction of the fission or fusion machinery can result in excessive mitochondrial fragmentation under neurodegenerative conditions, leading
to bioenergetic failure and subsequent synaptic damage.

28

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Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases

neuronal functions, including energy production, Ca2+

buffering, axonal and dendritic transport, and release
and re-uptake of neurotransmitter.3,5
In order to maintain a proper distribution of functional mitochondria, both fusion and fission must occur
in homeostatic balance. Basal activity of the fission
machinery is required to divide the mitochondrial network into transportable units which can then be efficiently distributed to synapses.3 Fusion is necessary
to maintain bioenergetic integrity of mitochondria.5
If the balance of fission and fusion becomes biased
(e.g., with increased fission or impaired fusion)
excessive mitochondrial fragmentation is observed,
resulting in impaired mitochondrial translocation
and energy production at synaptic sites (Fig. 1).1,3
The synaptic dysfunction thus induced is typically
followed by dendritic and axonal degeneration, leading to neurodegeneration. Indeed, excessive mitochondrial fragmentation with damaged cristae and
resulting impaired bioenergetics are often associated
with many neurological conditions, including stroke,
Alzheimers disease (AD), Parkinsons disease (PD),
and Huntingtons disease (HD), as well as several metabolic diseases.58 Pathological disturbance
of mitochondrial dynamics can result from either:
1) rare genetic mutations, such as those described for
Mfn1/2, Opa1 and Drp1, which underlie CharcotMarie-Tooth neuropathy type 2A (CMT2A),9 autosomal dominant optic atrophy (ADOA),6,10 and a
rare disorder of brain development,11 respectively; or
2) altered posttranslational modifications (PTMs) of
the proteins encoded by these genes that are responsible for the fission/fusion machinery.5,12
In this review, we discuss recent findings concerning aberrant PTMs which regulate the mitochondrial
fusion and fission machinery and thus contribute to
the pathophysiology of neurodegenerative diseases.
In particular, we focus on involvement of nitrosative stress-induced Drp1 activation, which results
in excessive mitochondrial fragmentation, impaired
bioenergetics, and consequent synaptic damage in
neurodegenerative disorders.7,12,13

Mitochondrial dynamics
inneurodegeneration

As mentioned above, tight regulation of the mitochondrial fission/fusion machinery is essential for
maintaining healthy neuronal physiology. However,
Journal of Cell Death 2013:6

dysfunctional mitochondrial dynamics caused by

impaired mitochondrial fission or fusion is a hallmark
of many neurodegenerative diseases and contributes
to their pathophysiology.

Impaired mitochondrial fission and fusion

in neurodegenerative diseases

Mitochondrial fusion is the process by which the inner

and outer mitochondrial membranes are separately
fused by Opa1 and Mfn1/2, respectively.3,6 Mutations
in these genes result in rare neurological conditions. For example, loss of function mutations in the
Mfn2 gene disrupts mitochondrial fusion, resulting in
distal muscle weakness and sensory loss in CMT2A.14
To date, more than 40 mutations have been identified,
most of which are located in the conserved GTPase
domain of Mfn2.9,15 In mouse models, deletion in the
mouse Mfn2 gene causes severe mtDNA loss and the
accumulation of mtDNA mutations.16 In addition,
Mfn2 deficiency results in decreased axonal transport of mitochondria, causing a lack of functional
mitochondria at pre- and postsynaptic sites.17 Collectively, these findings suggest that Mfn2 mutations in
CMT2A patients may trigger defects both in mtDNA
integrity and mitochondrial transport, contributing to
disease pathogenesis.
Another neurologic disorder caused by disruption in the fusion machinery is ADOA,6 representing
an hereditary optic nerve atrophy characterized by
degeneration of retinal ganglion cells and progressive loss of vision. Mutations in the Opa1 gene, and
to a lesser extent in Opa3, underlie ADOA.10 Similar to Mfn2 mutations, over 100 reported mutations
in Opa1 target predominantly the GTPase domain.18
Opa1 is located at the inner mitochondrial membrane, regulating fusion and modeling of the cristae structures. Interestingly, most Opa1 mutations
identified in the GTPase domain cause ADOA via a
dominant-negative effect. Furthermore, heterozygous
Opa1 knockout mice manifest severe degeneration of
the optic nerves, similar to human ADOA.19 Due to
decreased mitochondrial fusion activity, disruption
of Opa1 GTPase activity results in increased mitochondrial fragmentation, possibly making the retinal ganglion cells more susceptible to apoptosis.20,21
However, further analyses are needed to determine
whether mitochondrially-mediated apoptotic pathways are implicated in the pathogenesis of ADOA.
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Haun et al

Figure 2. Schematic of Drp1 domain structure and posttranslational modifications. Drp1 has a GTPase domain, a middle domain, an insert B domain,
and a GTPase effector domain (GED). Location of posttranslational modifications (PTMs) are indicated by P (phosphorylation), N (S-nitrosylation),
S (SUMOylation), or U (ubiquitination). The effect of PTMs on mitochondrial fission activity is indicated in green (activating) or red (inactivating).

Increased mitochondrial fragmentation due to

excessive fission is found in many neurodegenerative
disorders, including AD, PD and HD, as well as in
ischemic brain damage.5,22
Key players of the fission machinery are Drp1 and
Fis1. Drp1 consists of an N-terminal GTPase domain,
followed by a helical domain (also termed dynaminlike middle domain), an insert B domain, and a
C-terminal GTPase effector domain (GED) (Fig.2).
The helical domain allows Drp1 to form ring-like
oligomeric structures at the outer membrane of mitochondria to induce mitochondrial fission upon hydrolysis of GTP.5,23,24 A recent case study reported a rare
dominant negative mutation in the human Drp1 gene.11
This mutation inhibits Drp1 oligomerization and thus
results in the appearance of elongated mitochondrial
morphologies. These abnormal mitochondria lose
their respiratory function and can no longer be effectively distributed to regions of high-energy demand,
such as neuronal synapses.25 The dominant negative
Drp1 that results from this mutation caused impaired
brain development, microcephaly, optic atrophy, lactic academia, and eventual death by 37 days of age.11
Additionally, Drp1 activity can be tightly regulated by a series of PTMs including S-nitrosylation,
phosphorylation, SUMOylation and ubiquitination, as depicted in Figure 2. These PTMs generally
do not target the Drp1 GTPase domain but instead
are located within or in close proximity to the GED
domain, thereby allosterically influencing GTPase
activity.22
30

PTM regulation of Drp1 activity

and mitochondrial dynamics

Recently, we discovered that Drp1 is a target of

S-nitrosylation, a covalent modification of free thiol
by a nitric oxide (NO) group, forming an S-nitrosothiol
(R-SNO). Specifically, we found that S-nitrosylation
of Cys644 within the GED domain of Drp1 enhances
its GTPase activity and results in excessive mitochondrial fragmentation.12 S-Nitrosylation of Drp1 and its
involvement in neurologic disorders will be discussed
in detail in later sections.
In addition to S-nitrosylation, Drp1 undergoes multiple other PTMs including phosphorylation, SUMOylation, and ubiquitination. Among these Drp1 PTMs,
the effects of phosphorylation are perhaps best studied.
For example, it is known that phosphorylation of Drp1
at Ser616 by CDK1/cyclin B can increase its GTPase
activity.26 Consequently, Cdk1-dependent phosphorylation of Drp1 results in an increase in mitochondrial
fragmentation.26 In addition, cyclic AMP-dependent
protein kinase (PKA) phosphorylates Drp1 at Ser637
and decreases Drp1 activity by inhibiting molecular
interactions.27 PKA-mediated phosphorylation can
be counteracted by calcineurin-induced dephosphorylation of Ser637, resulting in translocation of Drp1
to the mitochondrial membrane.27,28 In an apparently
paradoxical manner, however, Calcium/calmodulindependent PKA 1 (CamKI) can phosphorylate the
same cysteine (Ser637) as PKA but rather induces
recruitment of Drp1 to the mitochondrial membrane
to form a complex with Fis1, resulting in increased
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Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases

mitochondrial fission.29 Therefore, additional studies

are needed to clarify the basis for the differential
effects of PKA and CamKI.
Drp1 activity is also be affected by SUMOylation,
which occurs within the insert B domain (Fig. 2). The
attachment of a small ubiquitin-related modifier 1
(SUMO1) to the lysine residues of Drp1 stabilizes the
protein and thus increases mitochondrial fragmentation.30 Several proteins, including SUMO1, Ubc9,
and MAPL, have been shown to mediate Drp1
SUMOylation.30,31 This stabilizing modification can
be reversed by sentrin/SUMO-specific protease
(SENP5).32,33 In addition to SUMOylation, the lysine
residues of Drp1 can be ubiquitinated. Parkin and mitochondrial E3 ligase protein MARCH5 can ubiquitinate
Drp1 on lysine residues located in the middle domain.
Initial studies reported that MARCH5 activity promoted mitochondrial fusion and elongation, suggesting that MARCH-dependent ubiquitination of Drp1
inhibited its activity.34,35 However, a subsequent report
by Karbowski et al.36 found that MARCH5 activity is
required for mitochondrial fission. Although one could
speculate that different expression levels of MARCH5
might cause these opposite effects, the physiological
action of MARCH5-mediated ubiquitination on Drp1
certainly warrants further investigation.
Additionally, parkin-mediated ubiquitination of
Drp1 results in its proteasomal degradation.37 Parkin
is a RING-type ubiquitin E3 ligase expressed in many
human tissues, including brain, heart, testis, and skeletal muscle.38 In the human brain, parkin is primarily expressed in neurons in various regions, including
the substantia nigra in the midbrain as well as in the
CA1/3 region of the hippocampus.39 Since mutations
in the parkin gene cause a familial form of PD,38 it is
tempting to speculate that abnormal regulation of the
parkin-Drp1 pathway, which would lead to impaired
mitochondrial dynamics, might contribute to the
pathogenesis of PD.

S-Nitrosylation, enhanced
mitochondrial fission, and
neurodegeneration
NO/reactive nitrogen species
and neurodegeneration

Over the past twenty years, numerous reports identified NO as a crucial protein-modifying molecule in
Journal of Cell Death 2013:6

cell biology, affecting many target proteins through

S-nitrosylation.40,41 Depending on the target protein,
the effects of S-nitrosylation can be quite diverse. NO
is typically generated from NO synthase (NOS) during the conversion of L-arginine to L-citrulline. NO
production can be controlled by transcriptional activation of inducible NOS (iNOS), or by Ca2+/calmodulin
dependent activation of neuronal or endothelial NOS
(nNOS or eNOS).42 A well-characterized pathway for
NO production in the nervous system occurs via activation of the N-methyl-D-aspartate-type glutamate
receptor (NMDAR).40,43 NMDAR stimulation results
in the influx of Ca2+, which, together with calmodulin,
stimulates nNOS to generate NO (Fig. 3).
Prior to the discovery of S-nitrosylation, initial
studies of NO signaling concentrated on its physiological and neuroprotective functions mediated by
activation of soluble guanylate cyclase (sGC) and
subsequent production of cGMP (Fig. 3). Subsequently, accumulating evidence has suggested that in
a variety of diseases, including AD, HD and PD, nitrosative and oxidative stress appear to trigger aberrant
S-nitrosylation events that contribute to neurodegeneration.40 For example, pathological S-nitrosylation
reactions include NO-mediated modifications to parkin and protein disulfide isomerase (PDI) (Fig. 3).4446
Additionally, we recently discovered that aberrant
S-nitrosylation of Drp1 hyperactivates its mitochondrial fission activity.12 In this case, NO triggers excessive mitochondrial fission accompanied by increased
autophagy (mitophagy) and decreased ATP production, which contributes to synaptic damage conditions
such as AD.12,47 In addition to SNO signaling pathways, NO can react with superoxide anion, generated
from mitochondrial as well as non-mitochondrial
sources (e.g., NADPH oxidase), to form peroxynitrite (ONOO-) (Fig. 3).48,49 Peroxynitrite can result
in lipid peroxidation and tyrosine nitration, another
NO-mediated PTM that causes pathological alteration
in target protein activity, as reviewed elsewhere.50

S-Nitrosylation of Drp1 and impaired

mitochondrial dynamics in AD and HD

AD is the most common neurodegenerative disorder with increasing prevalence because of the aging
demographic of our society. AD is clinically characterized by loss of cognitive functions accompanied
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Haun et al

Figure 3. NO signaling pathways in the nervous system. Left: Under physiological conditions, basal levels of NO from nNOS, stimulated by normal synaptic activity of N-methyl-D-aspartate-type glutamate receptors (NMDARs), provide neuroprotection via sGC/cGMP pathways as well as S-nitrosylation of
NMDARs and caspases. Right: Under pathophysiological conditions, overactivation of NMDARs, especially extrasynaptic NMDARs, results in increased
production of NO. Additionally, iNOS can generate toxic amounts of NO. Excessive NO can lead to S-nitrosylation of Drp1 (forming SNO-Drp1), which
contributes to neuronal synaptic injury via excessive mitochondrial fission and bioenergetic impairment. Additionally, S-nitrosylation of PDI, Parkin, XIAP,
and GAPDH can contribute to neurodegenerative disorders.

by intracellular neurofibrillary tangles, composed

of hyperphosphorylated tau, and extracellular amyloid plaques, comprised of amyloid- (A) peptide.
Soluble oligomers of A arise from the proteolytic
cleavage of amyloid precursor protein (APP) and are
thought to contribute to the pathogenesis of AD. Additional evidence accumulated over the past decade has
suggested that altered mitochondrial function associated with dysregulated mitochondrial dynamics is
another key feature of AD.13,47,51,52
Recently, the neurotoxic A oligomers were
reported to cause excessive mitochondrial fragmentation in cell-based models of AD.12 Specifically,
A oligomer-induced generation of NO resulted in
S-nitrosylation of Drp1 (forming SNO-Drp1), which
was found to hyperactivate its GTPase activity and
32

induce excessive mitochondrial fragmentation. The

resulting disruption of mitochondrial bioenergetics
caused a drop in ATP levels and consequent synaptic damage. Drp1 as shown to be S-nitrosylated at
cysteine residue 644, located in the GED domain.
Importantly, mutation of Drp1 Cys644 to an alanine
abrogated A/NO-induced mitochondrial fission,
consistent with the notion that the mitochondrial fragmentation was at least in part mediated by formation
of SNO-Drp1. In AD, the only neuropathological correlation with cognitive decline is the degree of synaptic loss. Interestingly, Drp1-C644A (representing a
nitrosylation-resistant mutant) prevented A-induced
synaptic damage, suggesting that S-nitrosylation
of Drp1 at Cys644 contributes to A toxicity in
AD. Moreover, the non-nitrosylatable Drp1 mutant
Journal of Cell Death 2013:6

Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases

p revented nitrosative stress-induced neuronal cell

death, lending support to the role of SNO-Drp1 in
NO-mediated neuronal damage.
Although this pathway of aberrant SNO-Drp1 formation was initially discovered in human AD brains
and animal models of AD, many other neurodegenerative conditions, including PD and HD, are characterized by increased oxidative and nitrosative stress.53
Consistent with this notion, SNO-Drp1 is present at very early stages in the substantia nigra of PD
animal models induced by pesticide exposure. Additionally, SNO-Drp1 appears to contribute to mutant
huntingtin (mtHtt)-induced neurotoxicity in cellbased and animal models of HD.54 HD is an adult
onset, genetic neurodegenerative disorder caused by
an aberrant expansion of a trinucleotide CAG repeat
in the htt gene. The CAG expansion, translated into
an expanded polyglutamine (polyQ) repeat in the
mtHtt protein, accelerates toxic misfolding of mtHtt,
leading to interference with several critical molecular cascades in the cell, and resultant degeneration of
synapses and neurons in the affected brain area (i.e.,
the striatum and cortex).
Similar to the effects of A oligomers on SNODrp1, expression of mtHtt significantly increased NO
production and subsequently up-regulated the levels
of SNO-Drp1 in primary cultures of cortical neurons.
Further along these lines, SNO-Drp1 formation was
considerably elevated in the striatum of a transgenic
mouse model of HD as well as in human postmortem
brains from HD patients.54 In a cell culture model of
HD, transfection of a non-nitrosylatable mutant form
of Drp1 abrogated the neurotoxic effects of mtHtt
on mitochondrial fragmentation and dendritic spine
damage, suggesting that SNO-Drp1 is a key mediator
of this form of mtHtt toxicity. Taken together, these
findings imply that S-nitrosylation of Drp1 may occur
in other neurodegenerative conditions, contributing
to aberrant mitochondrial dynamics and downstream
neuronal damage.

Conclusions and future directions

In the present study, we review how PTMs of Drp1,

particularly S-nitrosylation, may contribute to excessive mitochondrial fragmentation in neurodegenerative diseases. These findings strengthen the hypothesis
that aberrant protein S-nitrosylation may play a key
role in the contribution of mitochondrial pathology
Journal of Cell Death 2013:6

to many neurodegenerative diseases. Importantly,

the demonstration that preventing formation of
SNO-Drp1 can ameliorate A- or mtHtt-induced
synaptic damage in models of AD and HD, respectively, suggests a new therapeutic approach based
on developing drugs to affect disease-related protein
S-nitrosylation. Additionally, we anticipate that additional examples of aberrant S-nitrosylation as well as
other PTM events will be discovered which influence
mitochondrial dynamics and function in a number of
other neurodegenerative disorders.
Another important area for future research into
the effect of SNO-Drp1 concerns the discovery of
endogenous compounds, including nitrosylase and
denitrosylase enzymes which regulate its formation
and destruction. Related to this question, we recently
discovered that SNO-Cdk5 can act as an endogenous
nitrosylase, enhancing SNO-Drp1 levels via transnitrosylation of Drp1 (i.e., SNO-Cdk5 donates an NO
group to Drp1 to form SNO-Drp1).55 Further efforts
to identify additional molecular controls of aberrant
S-nitrosylation of Drp1 will be critical in determining
not only the downstream signaling consequences but
also for formulating new therapies for several neurological disorders.

Author Contributions

Wrote the first draft of the manuscript: FH and TN.

Agree with manuscript results and conclusions: FH,
TN, and SAL. Jointly developed the structure and
arguments for the paper: FH, TN, and SAL. Made critical revisions and approved final version: FH, TN, and
SAL. All authors reviewed and approved of the final
manuscript.

Funding

This work was supported in part by grants from the

Alzheimer Association (to TN), the Michael J. Fox
Foundation (to TN and SAL), and the NIH (P01
ES016738, P01 HD29587, and P30 NS076411) to
SAL.

Competing Interests

Author(s) disclose no potential conflicts of interest.

Disclosures and Ethics

As a requirement of publication the authors have provided signed confirmation of their compliance with
33

Haun et al

ethical and legal obligations including but not limited

to compliance with ICMJE authorship and competing
interests guidelines, that the article is neither under
consideration for publication nor published elsewhere,
of their compliance with legal and ethical guidelines
concerning human and animal research participants
(if applicable), and that permission has been obtained
for reproduction of any copyrighted material. This
article was subject to blind, independent, expert peer
review. The reviewers reported no competing interests. Provenance: the authors were invited to submit
this paper.

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