Journal of Inherited Metabolic Disease (2018) 41:585–596

https://doi.org/10.1007/s10545-018-0168-1

REVIEW

The role of suboptimal mitochondrial function in vulnerability

to post-traumatic stress disorder
Graeme Preston 1 & Faisal Kirdar 1 & Tamas Kozicz 1,2,3

Received: 20 October 2017 / Revised: 28 February 2018 / Accepted: 2 March 2018 / Published online: 28 March 2018
# SSIEM 2018

Abstract
Post-traumatic stress disorder remains the most significant psychiatric condition associated with exposure to a traumatic event,
though rates of traumatic event exposure far outstrip incidence of PTSD. Mitochondrial dysfunction and suboptimal mitochon-
drial function have been increasingly implicated in several psychopathologies, and recent genetic studies have similarly sug-
gested a pathogenic role of mitochondria in PTSD. Mitochondria play a central role in several physiologic processes underlying
PTSD symptomatology, including abnormal fear learning, brain network activation, synaptic plasticity, steroidogenesis, and
inflammation. Here we outline several potential mechanisms by which inherited (genetic) or acquired (environmental) mito-
chondrial dysfunction or suboptimal mitochondrial function, may contribute to PTSD symptomatology and increase suscepti-
bility to PTSD. The proposed pathogenic role of mitochondria in the pathophysiology of PTSD has important implications for
prevention and therapy, as antidepressants commonly prescribed for patients with PTSD have been shown to inhibit mitochon-
drial function, while alternative therapies shown to improve mitochondrial function may prove more efficacious.

Incidence and prevalence of PTSD hyperarousal — symptoms pointing to potential defects in

and traumatic event exposure
Post-traumatic stress disorder (PTSD) is a debilitating psy-
chiatric condition that affects millions of individuals world-
wide. The current DSM-V requires an individual be exposed
— either directly or indirectly — to a traumatic event in the
form of actual or threatened death, serious injury, or sexual
violence, to oneself or a close family member, or to repeat-
ed exposure to the details of such a traumatic event.
Diagnosis requires the presence of symptoms of three types:
intrusive symptoms (such as memories, dreams, and flash-
backs) associated with the traumatic event, symptoms of
avoidance, and symptoms of hypervigilance and
Communicated by: Eva Morava
* Graeme Preston
gpreston@tulane.edu
1
Hayward Genetics Center, Tulane University School of Medicine,
1430 Tulane Ave, New Orleans, LA 70112, USA
2
Department of Clinical Genomics, Mayo Clinic, Rochester, MN,
USA
3
Department of Anatomy, Radboud University Medical Center,
Nijmegen, Netherlands
neural circuits related to fear learning, threat detection, con-
text processing, and executive function (Shalev et al 2017;
Flory and Yehuda 2015). While the cause of the disorder —
experience of a traumatic event (TE) — remains clear, a
robust description of the etiology of PTSD remains elusive.
For a given individual, the estimated risk of developing
PTSD following trauma exposure can vary from 1% to
greater than 50% (Spoont et al 2015). Lifetime prevalence
of PTSD worldwide varies from 1.3 to 12.2%; the 1-year
prevalence varies from 0.2 to 3.8%. And while PTSD sus-
ceptibility varies between high- and low-income countries,
and occurs more frequently in soldiers, first responders and
other groups regularly exposed to trauma, these differences
may be the result of differences in traumatic event exposure,
or social factors, rather than due to some underlying biolog-
ic factor (Karam et al 2014, Shalev et al 2017). The severity
of TE does not appear to be predictive of subsequent PTSD
severity (Karam et al 2014, Rubin and Feeling 2013); how-
ever, the number of TEs experienced appears to be highly
predictive of PTSD susceptibility and symptom severity,
with PTSD associated with 4 or more TEs (4+/PTSD)
showing significantly greater PTSD vulnerability and more
severe symptomatology compared to PTSD associated with
3 or fewer TEs (3-/PTSD) (Karam et al 2014, Benjet et al
2015). There are also data to suggest that TE type may
586
predict PTSD vulnerability (Ozer et al 2003, Roberts et al
2011, Kessler et al 2014). Interestingly, those TE types most
predictive of PTSD vulnerability, such as sexual assault and
physical violence are also those TEs most associated with 4
+/PTSD, and those highly predictive TE types may be as-
sociated with revictimization and multiple TE exposure
(Karam et al 2014, Benjet et al 2015). The incidence of
trauma, notably, remains much more prevalent than that of
PTSD, and most individuals exposed to a TE do not devel-
op PTSD: 64–70% of adults worldwide experience a TE at
some time in their lives and 31% experience four or more
events, though under-reporting of TE exposure is expected
(Shalev et al 2017; Benjet et al 2016). Based on this epide-
miologic data, it seems likely that an underlying physiolog-
ic, genetic, or neurologic vulnerability factor exists.
Identified genetic susceptibility factors
for PTSD
Early genetic studies into PTSD vulnerability focused on
genes involved in neurotransmitters and endocrine brain ef-
fectors, including serotonin, dopamine, glucocorticoids, and
GABA, among others; however, results were inconsistent
(Broekman et al 2007). A recent study using a gene expression
panel focusing on mitochondrial genes in the prefrontal cortex
of post-mortem brains from six PTSD patients and six controls
showed altered expression of eight mitochondria-related
genes, including six genes of the OXPHOS pathway, three
genes of the TCA cycle, and three genes of the pyruvate path-
way (Su et al 2008). In a group of 87 male combat veterans,
mitochondrial DNA copy number was reduced in
granulocytes of PTSD-affected individuals compared to unaf-
fected individuals, and was significantly correlated with pos-
itive affectivity (Bersani et al 2015). A subsequent study of
978 single nucleotide polymorphisms in the mtDNA of 1238
individuals showed significant correlation between PTSD se-
verity and the heteroplasmy levels in leukocytes of two
mtDNA SNPs in genes for respiratory chain proteins
(Flaquer et al 2015).
These pieces of genetic evidence for mitochondrial in-
volvement in PTSD imply that mitochondrial dysfunction
may play a role in the etiology of PTSD (Jou et al 2009).
We argue that mitochondria could play crucial roles in many
of the physiologic processes involved in PTSD symptomatol-
ogy, including hypocortisolemia, activation/inhibition of brain
networks involved in fear learning and extinction; neuronal
plasticity including neurogenesis, apoptosis, and synaptic ar-
chitecture (Cheng et al 2010); the regulation of stress hormone
production and release (Miller 2013; Smith and Vale 2006);
and inflammatory response (Lopez-Armada et al 2013). Here,
we outline several mechanisms by which mitochondrial dys-
function or suboptimal mitochondrial function (SMF) may
J Inherit Metab Dis (2018) 41:585–596
contribute to PTSD susceptibly by influencing these biologi-
cal domains of PTSD pathophysiology Fig. 1.
Allostasis, allostatic load, stress, and brain
mitochondria
Mitochondria are the primary metabolic organelles of eukary-
otic organisms, and responding to a stressful environment,
such as exposure to a traumatic event, requires energy.
Living organisms continually attempt to maintain homeosta-
sis, a physiologic state in which metabolic functions are kept
within an optimal range of parameters necessary to support the
essential functions of life in the face of ever-changing envi-
ronments. It often occurs, however, that a living thing encoun-
ters some environmental condition beyond what its normal
homeostatic functions can accommodate. In this case, physi-
ologic parameters must be altered in such a way to retain its
ability to restore homeostasis. This process is known as
allostasis (McEwen 1998). Allostasis is an essential process
for maintaining life functions through the various stages of a
normal life span. The process of undergoing allostasis, the
allostatic state, is necessarily hallmarked by an imbalance of
the biochemicals that mediate the change, such as corticoste-
roids, cytokines and catecholamines (McEwen and Wingfield
2003). The combined energetic and physiologic requirements
to complete allostasis are known as allostatic load. If there are
insufficient resources to achieve the necessary allostatic
change (the allostatic load is too great), or if the allostatic
change is inhibited by some other mechanism or does not
reach its proper end-point, and homeostatic capacity is not
restored, a state of allostatic overload can result (McEwen
and Wingfield 2003; Picard et al 2014).
The potential hazards of allostatic load are of particular
significance to the brain. Allostatic state is a highly ener-
getic process, and the brain is a highly energetic organ.
Constituting only 2% of the human body mass by weight,
the brain is responsible for 20% of the total energy me-
tabolism of the body (Harris et al 2012). Mitochondria
play a central role in stress response and allostasis, par-
ticularly in the brain (Picard et al 2014; Jou et al 2009).
One of the primary biological functions of mitochondria
is the production of usable cellular energy in the form of
ATP through oxidative phosphorylation (OXPHOS) by
the enzymatic complexes of the electron transport chain,
a pathway responsible for 90% of the cellular energy pro-
duction in the human body (Chance et al 1979).
Mitochondria are also instrumental in calcium ion (Ca2+)
sequestration (Rizzuto et al 2012), fatty acid oxidation
(Wanders et al 2010), nucleic acid metabolism (Wang
2016), are the primary producers of ROS production
(Murphy 2009), and are the prime mediators of apoptotic
cell death (Wang and Youle 2016). Mitochondria undergo
J Inherit Metab Dis (2018) 41:585–596
Fig. 1 Mitochondrial dysfunction, either inherited (genetic) or acquired
(environmental), disrupts production of cellular energy (ATP), buffering
of cytosolic Ca2+, ROS production, and mitochondrial fission and fusion,
fission and fusion, and the formation and fracturing of
these fused mitochondrial superstructures is directly relat-
ed to cellular metabolic function, and promotes cell sur-
vival, particularly in response to stress (Friedman and
Nunnari 2014). Each mitochondrion possesses thousands
of copies of its own genome, and while most of the genes
coding for the ~1500 mitochondrial proteins have been
relocated to nuclear chromosomes, the mitochondrion re-
tains 22 tRNA genes, and 13 protein-coding genes, all
essential equipment for mitochondrial gene transcription
and assembly of the electron transport chain (Taanman
1999). Exposed to the highly oxidative environment of
the mitochondrial matrix, and without the DNA repair
mechanisms of the nucleus, the mitochondrial genome is
highly susceptible to oxidative damage and DNA muta-
tion (Shokolenko et al 2009). These nucleoid genomes
can be reshuffled through mitochondrial fission and fu-
sion, diluting deleterious mutations, potentially mitigating
the resultant bioenergetic disruptions. Mitochondrial mu-
tations induced by oxidative damage can result in mito-
chondrial dysfunction resulting in additional oxidative
damage (Cui et al 2012). The delicate balance of mito-
chondrial function can easily be disrupted, causing a cas-
cade of disfunction which can ultimately result in apopto-
tic cell death, necrosis, or severe cellular disfunction
(Marchi et al 2012). Patients with inherited mitochondrial
dysfunction or SMF may have sufficient mitochondrial
capacity to meet the energetic needs of their day-to-day
lives, but may have insufficient mitochondrial capacity to
respond to a highly stressful environment like a traumatic
event exposure. Alternatively, mounting a physiologic re-
sponse to a traumatic event exposure may induce addi-
tional mitochondrial dysfunction in patients with inherited
mitochondrial dysfunction or SMF.
PTSD, hypocortisolemia, and mitochondria
Glucocorticoid hormone release is a key aspect of stress
response, with plasma concentrations of glucocorticoids
peaking 15–30 min following a stressful stimulus and
returning to pre-stress levels after 60–90 min (de Kloet
587
resulting in abnormal physiologic response to stress in the neurons of the
brain, contributing to PTSD symptomatology, and increasing vulnerabil-
ity to PTSD
et al 2005). These corticosteroid hormones have been
shown to alter the function and structure of the brain,
influencing neurogenesis, neural atrophy, cell turnover,
and neural physiology and excitability (Datson et al 2001;
Gould et al 1990; Sloviter et al 1989; Hu et al 1997;
Wossink et al 2001; Nair et al 2004; Almeida et al 2017;
Diamond et al 1992; Kim and Diamond 2002; Pavlides
et al 1993; Xu et al 1997). The physiologic effects of
glucocorticoids are of great importance to the understanding
of PTSD. Paradoxically, patients with PTSD show reduced
levels of plasma cortisol (hypocortisolaemia) and increased
levels of corticotropin-releasing hormone (CRH) in cerebro-
spinal fluid (Baker et al 1999), indicating an HPA axis
dysregulation. Mitochondria play potentially pathogenic
roles in many of the steps of HPA axis-mediated glucocor-
ticoid release and regulation (Chow et al 2017).
Glucocorticoid synthesis takes place within mitochondria
of the steroidogenic cells of the adrenal cortex, and is de-
pendent on enzymes responsible for sensing cholesterol on
the outer mitochondrial matrix, transport of the cholesterol
into the mitochondrial matrix, and the ultimate synthesis of
glucocorticoids from cholesterol (Miller 2013). Primary ad-
renal insufficiency (Addison’s Disease) has been reported in
mitochondrial disease cases with mtDNA mutations, oxida-
tive phosphorylation defects, and large scale mtDNA dele-
tions (North et al 1996; Nicolino et al 1997; Bruno et al
1998; Boles et al 1998; Artuch et al 1998). Steroid hor-
mone synthesis by steroidogenic cells of the adrenal cortex
is stimulated by binding of adrenocorticotropic hormone
(ACTH) to melanocortin type-2 receptors (MCR-2) and
subsequent Ca2+ influx and cAMP induction (Kojima
et al 1985; Durroux et al 1991; Yamazaki et al 1998).
However, maintenance of optimal steroidogenic capacity
requires chronic activation by ACTH, and prolonged enzy-
matic induction by cAMP activation (Simpson and
Waterman 1988). Mitochondrial dysfunction or reduced mi-
tochondrial capacity may allow for sufficient Ca2+ buffering
to facilitate the initial glucocorticoid synthesis induced by
ACTH activity in response to stress, but may be insuffi-
cient to reliably maintain that buffering capacity in response
to chronic, long term ACTH activation, resulting in ste-
roidogenic dysfunction and hypocortisolemia.
588
PTSD, neuronal circuits of fear,
and mitochondria
PTSD represents an abnormal response to a stressful environ-
ment (de Kloet et al 2005). Abnormal activity in the neural
circuits associated with a healthy stress and fear response,
including fear and safety learning, threat detection, executive
function and emotional regulation, and contextual processing,
may play a significant role in the pathophysiology of PTSD
(Shalev et al 2017, VanElzakker et al 2014, Quirk and Mueller
2007, Hayes et al 2012, Liberzon and Abelson 2016, Olff et al
2014, Aupperle et al 2012, Polak et al 2012).
Consolidation of fear memory is crucial for an animal’s
defense against threats. The consolidation of memories asso-
ciated with fear has been repeatedly mapped to the amygdala
and is dependent upon neuroplasticity in that area (Fanselow
and LeDoux 1999). Closely related to fear conditioning is the
process of fear extinction, a progressive reduction in fear re-
sponse to a previously dangerous environment in which no
adverse conditions result (Myers and Davis 2007). Inefficient
fear extinction in patients with PTSD results in exaggerated
fear response in situations reminiscent of trauma, and leads to
symptoms of hyperarousal and increased startle response
(Francati et al 2007). Ca 2+ -dependent post synaptic
long-term potentiation (LTP) is instrumental in both the con-
solidation of fear memories (Huang and Kandel 1998) as well
as fear extinction (Charney 2004). Fear extinction involves
inhibition of the amygdala (LeDoux 1993), and functional
neuroimaging studies have shown increased activity in the
amygdalae of patients with PTSD (Liberzon et al 1999;
Pissiota et al 2002; Shin et al 1997; Hendler et al 2003;
Yang et al 2004; Shin et al 2004) suspected to result in defi-
cient fear extinction and subsequent hyperarousal (Bremner
et al 1995). Initial activation of the amygdala is modulated
by the medial prefrontal cortex (mPFC), and insufficient in-
hibitory feedback may result in the hyperactivation of the
amygdala in PTSD patients (Nutt and Malizia 2004).
Amygdalar inhibition by the mPFC is mediated by GABA
inter-neurons (Charney 2004), high energy neurons character-
ized by repetitive, high frequency action potentials (Kann et al
2014). To maintain the ion gradients required for this activity,
GABA interneurons consume significantly more cellular en-
ergy than other cell types in the brain, and contain a high
density of mitochondria and cytochrome oxidase (Kageyama
and Won-Riley 1982; Gulyas et al 2006). These cells are sub-
sequently highly sensitive to defects in the mitochondrial re-
spiratory chain (Kann et al 2011; Whittaker et al 2011), and
interneuron dysfunction and loss have been implicated in the
neuropathology of patients with mitochondrial disease. A
2014 study found several up- and down-regulated genes in
the amygdalae of rats with PTSD characterized by exaggerat-
ed startle, several of which have previously been associated
with neuronal dysfunction, psychiatric disorders, and stress
J Inherit Metab Dis (2018) 41:585–596
response (Li et al 2014). A subsequent 2015 study found 34
genes related to mitochondria upregulated in the amygdalae of
stressed rats (Zhang et al 2015). Pharmacologic increase in
mitochondrial cytochrome oxidase activity has been shown
to increase fear extinction (Telch et al 2014). The glutamate
receptor N-methyl-D-aspartate (NMDA) acts as a calcium ion
channel; buffering of intracellular Ca2+ levels by mitochondria
is crucial for NMDA-mediated neuronal activation, and dys-
functional mitochondrial Ca2+ buffering has been implicated
in NMDA-mediated excitotoxicity and irreversible neuronal
damage and loss (Peng et al 1998). NMDA-mediated neuronal
activation also induces the production of reactive oxygen spe-
cies (ROS) and nitric oxide by mitochondria, which may be
responsible for NMDA-mediated excitotoxicity (Dugan et al
1995; Gunasekar et al 1995; Reynolds and Hastings 1995).
Maintenance of proper ROS levels has also been shown to
mediate GABA-ergic inhibitory signaling (Accardi et al
2014). We propose that mitochondrial dysfunction, or subop-
timal mitochondrial function (SMF), results in disrupted or
dysfunctional signaling by GABA-ergic interneurons respon-
sible for inhibition of the amygdala by the medial prefrontal
cortex, and subsequent fear extinction, leading to the persis-
tent and inappropriate fear response characteristic of PTSD,
either through insufficient cellular energy to maintain proper
ion gradients, deficient Ca2+ buffering leading to aberrant
NMDA mediated signaling, disrupted levels of ROS, or some
combination of these effects.
PTSD, inflammation, and mitochondria
Altered inflammatory markers have been repeatedly identified
in patients with PTSD. Increased concentrations of the
pro-inflammatory cytokines IL-1β, TNFα, IL-2, IL-6,
Interferon gamma (INF-y), and C-reactive protein (CRP) are
all associated with trauma exposure (Tursich et al 2014). The
inflammatory response is tightly associated with mitochondri-
al function: mitochondria can induce an inflammatory re-
sponse as part of the innate immune response, and inflamma-
tion can influence mitochondrial function (Lopez-Armada
et al 2013). A primary mediator of the inflammatory response
is ROS production, which can activate the NLRP3
inflammasome (Kepp et al 2011). Ros production induced
by mitochondrial dysfunction can lead to activation and secre-
tion of IL-1β (Strowig et al 2012). Inhibition of ATP synthesis
by oligomycin, which has been shown to increase ROS pro-
duction (Tan et al 1998) increased the sensitivity of IL-1β
tenfold in human sinoviocytes (Valcarcel-Ares et al 2014).
Degraded mtDNA has been shown to induce IL-1β, IL-6,
and TNFα in mouse astrocytes (Mathew et al 2012).
Pro-apoptotic signaling promotes release of IL-1β in mouse
macrophages (Nakahira et al 2011). Both IL-1β and TNFα
inhibit complex I activity and ATP synthesis, resulting in
J Inherit Metab Dis (2018) 41:585–596
increased ROS production in human lymphocytes (Guidarelli
et al 2007, Kim et al 2010), and complex I deficiency can
induce IL-1β in the hypothalamus (Yi et al 2007). IL-6 can
increase dopamine activity in the amygdala and hippocampus,
and may influence consolidation and extinction of fear learning,
and context processing (Pervanidou et al 2007). Increased IL-6
levels have been implicated in the development of PTSD in
children following motor vehicle accidents (Pervanidou et al
2007). INF-y has been shown to inhibit the expression of
SIRT1, an important regulator of mitochondrial biogenesis
and turnover (Li et al 2012). Cytokine levels also appear to
directly influence the pathophysiology of PTSD. In patients
with PTSD, TNFα and CRP levels correlate with PTSD symp-
tomatology generally (von Kanel et al 2007, Michopoulos et al
2015), and TNFα levels correlate with avoidance,
re-experiencing, and hyperarousal specifically (von Kanel et al
2007). TNFα inhibits LTP in the CA1 and dentate gyrus regions
of the hippocampus in a partially MAPK-dependent manner
(Butler et al 2004). Increased levels of circulating IL-1, IL-6,
TNFα, and CRP have also been identified in patients with major
depressive disorder (MDD) (Dowlati et al 2010) and reduced
hippocampal volumes similar to those observed in PTSD pa-
tients have been reported in MDD patients with high levels of
IL-6 and CRP (Frodl and Amico 2014). Immune challenge in
healthy individuals induced increased levels of TNFα, IL-6 and
IL-1, and decreased levels of brain derived neurotrophic factor
(BDNF) in the hippocampus (Dunn et al 2005), while also
increasing TNFα levels in the PFC (Feleder et al 2010), and
decreasing connectivity between the ACC, mPFC, and amyg-
dala (Frodl and Amico 2014), resulting in impaired learning and
memory (Dunn et al 2005). We propose that mitochondrial
dysfunction or SMF may increase an individual’s susceptibility
to the kinds of abnormal inflammatory response observed in
patients suffering from PTSD, and that this abnormal inflamma-
tory response may contribute to PTSD symptomatology.
PTSD, neuronal plasticity, and mitochondria
Mitochondria play an important role in synaptic plasticity by
facilitating neurogenesis, neuron remodeling, and neurotransmit-
ter release, as well as providing the cellular energy required for
the gene regulation changes, protein synthesis, cytoskeletal re-
modeling, organelle trafficking, and intracellular transport re-
quired for these processes (Cheng et al 2010). Neurogenesis is
a highly energetic process, requiring large-scale cytoskeletal re-
arrangement, organelle transport, and neuronal sprouting, mak-
ing adequate mitochondrial function essential (Xavier et al 2015).
Neuronal differentiation, a crucial step in neurogenesis, is marked
by an increase in mitochondrial mass (Cheng et al 2010), as well
as key mitochondrial proteins and transcription factors (Mattson
and Liu 2003; Kann and Kovacs 2007). The differentiation of
neuronal stem cells into functional neurons involves shifts in
589
mitochondrial bioenergetics, mitochondrial dynamics (fission
and fusion), Ca2+ homeostasis, ROS production, and subcellular
mitochondrial distribution (Prigione et al 2010; Voccoli and
Colombaioni 2009). Levels of PGC1α, the primary regulator
of mitochondrial biogenesis, are increased in neural progenitor
cells and newly-developed neurons in brains of developing rats
(Cowell et al 2007), and PGC1α-knockout mice display loss of
brain matter and behavioral anomalies (Lin et al 2004).
Mitochondrial uncoupling protein (UCP) has recently been
shown to mediate ATP production, ROS production, and
Ca2+ homeostasis (Chan et al 2006; Liu et al 2006), and
neuron-specific UCP has been implicated in regulating
neuronal differentiation (Smorodchenko et al 2009).
Differentiation-inducing transcription factors influence
regulation of several mitochondrial genes, including genes
for mitochondrial transport, and are highly involved in
neurite outgrowth (Baxter et al 2009). Mitochondria appear
to be instrumental in all phases of neurite outgrowth, from
determination of the neuronal axis (Mattson and Partin
1999) to extension of the axon (Ruthel and Hollenbeck
2003; Dedov et al 2000), a role that goes beyond simple
production of ATP and which may involve mitochondrial
Ca2+ buffering and its effects on cytoskeletal reorganiza-
tion (Mattson and Partin 1999). Localized treatment with
nerve growth factor (NGF) induces actin-dependent trans-
port and retention of mitochondria to the site of NGF in-
fusion, and an increase in mitochondrial membrane poten-
tial (Verburg and Hollenbeck 2008; Chada and Hollenbeck
2004). Evidence suggests that mitochondrial dysfunction
has an even greater effect on dendritic morphology than
axon morphology, as induced mitochondrial dysfunction
insufficient to significantly disrupt axonal morphology sig-
nificantly disrupted dendritic tree formation (Chihara et al
2007). Mitochondria are significantly more active in the
dendrites than in the axons of cultured hippocampal neu-
rons (Overly et al 1996). Activation of post-synaptic glu-
tamate receptors such as NMDA and AMDA (a—
amino-3-hydroxy-5-methylisoxazole-4-propionic acid) in-
duces significant influx of extracellular and endoplasmic
reticulum Ca2+ into the cytosol (Toresson and Grant 2005)
which must be sequestered by mitochondria (Duchen
2000; Nicholls and Budd 2000; Toescu 2000). The number
of mitochondria in the dendritic spines, where synaptic activa-
tion occurs, increases in response to repeated depolarization,
and this redistribution of mitochondria is facilitated by mito-
chondrial fission and fusion (Li et al 2004). NMDA is a potent
mediator of LTP (Lüscher and Malenka 2012) and has been
shown to be important in memory and learning (Williams
et al 1998; Calabresi et al 2001; Li et al 2010). Induction of
LTP in the dentate gyrus of rats induced expression of several
mitochondrial genes within the dentate gyrus, as well as in
neighboring regions of the hippocampus where LTP had not
occurred (Williams et al 1998). Mitochondrial activation of
590
caspase-9 and caspase-3 in dendrites, independent of apoptotic
cell death, facilitates AMDA receptor internalization and sub-
sequent long-term depression (LTD) without effecting LTP (Li
et al 2010). BDNF is a potent inducer of LTP in hippocampal
neurons (Ying et al 2002) and has been shown to be instrumen-
tal in hippocampal learning and memory (Lu et al 2009). Both
glutamate and BDNF are important mediators of synaptic
neurogenesis, synaptic plasticity, and neuronal structure
(Martin and Finsterwald 2011). Activation of glutamate recep-
tors in hippocampal neurons increased glucose metabolism
(Shuttleworth et al 2003), and BDNF promotes increased glu-
cose utilization by neuronal mitochondrial in response to in-
creased energy demand (Burkhalter et al 2003) and increased
mitochondrial complex I activity (Markham et al 2004).
While necrotic cell death has historically been implicated in
neurodegenerative disease, apoptotic cell death is increasingly
recognized as the primary mediator (Tatton and Olanow 1999).
The intrinsic apoptotic pathway is initiated by mitochondria,
which release cytochrome c into the cytosol, triggering the cas-
pase cascade that results in apoptotic cell death (Reed 1997;
Green and Reed 1998; Varfolomeev et al 1998; Juo et al 1998;
Kuida et al 1998; Hakem et al 1998). The intrinsic apoptotic
pathway is controlled by the Bcl-2 family of proteins, which
may have either pro- or anti-apoptotic effects; the ratio of Bcl-2
family species ultimately dictates the sensitivity of a cell to var-
ious pro- or anti-apoptotic signaling (Chen et al 1996, Middleton
et al 1996, Song et al 1999, Inohara et al 1998). In hippocampal
neurons, activation of the NMDA receptor by L-glutamate in-
creases elevated cytosolic Ca2+, inducing BAD/Bcl2-induced
apoptosis (Wang et al 1998). Apoptotic cell death mediated by
Bcl-2 family proteins has been identified in numerous psycho-
logical disorders including Alzheimers (MacGibbon et al 1997).
Ultimately, Bcl-2 family proteins mediate the intrinsic apoptotic
pathway by controlling the release of cytochrome c from the
mitochondria, with pro-apoptotic Bcl-2 family proteins facilitat-
ing release, and anti-apoptotic species inhibiting its release. In
addition to cytochrome c, mitochondria contain several addition-
al pro-apoptotic species within their intermembrane space, which
aid in the induction of apoptotic cell death in the event of Blc-2
family protein mediated apoptosis induction or mitochondrial
damage (Mancini et al 1998; Krajewski et al 1999; Susin et al
1999; Du et al 2000; Verhagen et al 2000). Mitochondria are
very susceptible to oxidative stress: nitric oxide, lipid peroxida-
tion, and ROS can lead to oxidative stress, which can result in
loss of mitochondrial membrane potential, respiratory chain dis-
ruption, and decreased ATP production (Kroemer and Reed
2000; Brown 2003). Ca2+ influx in both pre-synaptic axon ter-
minals and post-synaptic dendrites can induce significant oxida-
tive and metabolic stress on mitochondria (Bezprozvanny and
Mattson 2008). This process of mitochondrial dysfunction and
oxidative damage can be self-catalyzing, with oxidative stress
disrupting mitochondrial function, which induces further oxida-
tive stress. Patients with congenital or acquired mitochondrial
J Inherit Metab Dis (2018) 41:585–596
dysfunction, who experience a stressor, may experience a pro-
gressive degeneration of mitochondrial function, which could
disrupt otherwise healthy neurogenesis, neuronal differentiation,
neurite outgrowth, synaptic plasticity, and LTP, and may disrupt
the balance of pro-and apoptotic factors, leading to cell
death-induced neuropathy and psychopathology.
Therapeutic implications
The proposed roles of mitochondrial dysfunction in the above
outlined biological domains of PTSD pathophysiology and
susceptibility to PTSD have several implications for treat-
ment, management, and prevention. Current treatment for
PTSD focuses on antidepressant (AD) drug therapies that alter
neurotransmissions by serotonin, dopamine, and norepineph-
rine. Currently, the selective serotonin reuptake inhibitors
(SSRIs) Sertraline and Paroxetine are the only
FDA-approved drug treatments for PTSD, and are the pre-
ferred initial class of medications used to treat PTSD (Brady
et al 2000; Marshall et al 2001). Additional antidepressants
commonly prescribed as first-line treatments for PTSD in-
clude fluoxetine, mirtazapine, venlafazine, and nefazodone.
Tricyclic antidepressants and monoamine oxidase inhibitors
(MAOIs) can be used as second-line treatments. Several
ADs show diverse adverse effects on mitochondrial function,
including energy metabolism and apoptosis. Fluoxetine in-
hibits OXPHOS in rat brain and liver mitochondria by affect-
ing electron transport and ATP synthesis (Souza et al 1994;
Curti et al 1999). Fluoxetine and paroxetine increase apoptosis
in glioma and neuroblastoma cells in vitro (Levkovitz et al
2005). Mirtazapine inhibited complex I activity in mitochon-
dria isolated from pig brain in vitro (Hroudova and Fisar
2010). Acute in vitro treatment with SSRIs, SNRIs, and
MAOIs decreased mitochondrial bioenergetics (Klinedinst
and Regenold 2015). We have outlined several potential
mechanisms by which mitochondrial dysfunction or reduced
mitochondrial capacity could increase a patient’s susceptibili-
ty to PTSD or exacerbate PTSD symptoms. In such cases, the
use of ADs with known mitochondrial interactions should be
avoided, to avoid inducing further mitochondrial dysfunction.
A mitochondrial dysfunction mechanism of PTSD suscepti-
bility has several implications in terms of novel PTSD preven-
tion and treatment. Recent developments in the metabolic pro-
filing have introduced the potential to screen for mitochondri-
al disease patients, and biomarkers for mitochondrial dysfunc-
tion may help identify PTSD-susceptible individuals in at-risk
populations (Thompson Legault et al 2015). Additionally, in-
formation about an SMF patient’s metabolic profile could
suggest personalized metabolic interventions and greatly im-
prove recovery outcomes (Parr and Martin 2012). Lifestyle
and dietary interventions like increased exercise, caloric re-
striction, and cognitive enrichment, which have been shown
J Inherit Metab Dis (2018) 41:585–596
to improve mitochondrial capacity and mitochondrial health
(Lopez-Lluch et al 2006, Lanza et al 2012, Eluamai and
Brooks 2013, Menshikova et al 2006), and which have been
shown to be neuro-protective (Maalouf et al 2009; Zigmond
and Smeyne 2014; Milgram et al 2006), may offer alternative
therapeutic strategies which avoid drug-induced mitochondri-
al inhibition or dysfunction. Increased physical activity is as-
sociated with a decreased incidence of psychopathology, and
studies have shown that exercise can be used as a possible
treatment for anxiety and depression, though the mechanism
is not fully understood (Strohle 2009).
Outstanding questions
Mitochondrial dysfunction and suboptimal mitochondrial
function have been increasingly implicated in several psycho-
pathologies, and recent genetic studies have similarly sug-
gested a pathogenic role of mitochondria in PTSD.
Mitochondria play a central role in several physiologic pro-
cesses underlying PTSD symptomatology, including abnor-
mal fear learning, brain network activation, synaptic plasticity,
steroidogenesis, and inflammation. Not surprisingly, PTSD
shares many of these pathophysiologic features with other
psychopathologies associated with mitochondrial dysfunc-
tion. Anxiety disorders have been associated with abnormal
fear learning, inappropriate neuronal activation (viz. in the
amygdala, medial prefrontal cortex, and hippocampus), and
HPA axis dysregulation (Craske et al 2017). There is growing
evidence that abnormal inflammatory signaling secondary to
mitochondrial ROS production plays a role in the pathophys-
iology of schizophrenia (Rajasekaran et al 2015). Given the
large degree of overlap in pathophysiologic pathways among
anxiety and mood disorders, it is perhaps not surprising that in
a national comorbidity survey of 12-month DSM-IV disor-
ders, PTSD showed a high comorbidity with all anxiety and
mood disorders investigated (Kessler et al 2005). Ultimately,
psychopathologies appear to precipitate from a complex inter-
action of genetic, physiologic, and environmental factors.
While further investigation will be required to elucidate exact-
ly how any one particular collection of these overlapping ge-
netic, physiologic, and environmental factors combines to pre-
cipitate a particular psychopathology, current evidence sug-
gests that mitochondrial dysfunction plays a significant and
important role in vulnerability to PTSD, perhaps by some of
the same pathways that lead to increased vulnerability to anx-
iety and mood disorders, as well as other psychopathologies.
It may prove that traumatic event exposure, which plays a
unique role in the precipitation of PTSD as opposed to other
psychopathologies, and abnormal physiologic processes asso-
ciated with response to that traumatic event exposure — such
as steroid hormone release and signaling — secondary to mi-
tochondrial dysfunction, may prove to play a significant role
591
in determining whether a patient with mitochondrial dysfunc-
tion or SMF develops PTSD-like symptomatology rather than
symptomatology consistent with anxiety or mood disorder.
We have provided evidence that mitochondrial dysfunction
is associated with PTSD susceptibility, and have provided
several mechanisms by which mitochondrial dysfunction
may contribute to the pathophysiology of PTSD. We have also
cited mechanisms by which stress can induce mitochondrial
dysfunction, particularly in individuals who already display
reduced mitochondrial capacity. If mitochondrial capacity
does in fact play a causal role in the psychopathology of
PTSD, and contributes to PTSD susceptibility, additional in-
vestigation will be required to determine whether this mito-
chondrial dysfunction or suboptimal mitochondrial function is
congenital or acquired, and whether this mitochondrial dys-
function can be induced by the stress of a traumatic event
exposure. Both inborn and induced mitochondrial dysfunction
have been shown to induce susceptibility to anxiety and mood
disorders, which share significant pathophysiology’s to
PTSD. Pharmacologic inhibition of mitochondrial complex I
and II has been shown to induce anxiety-like behavior in mice
(Hollis et al 2015), while mice harboring a defective mtDNA
polymerase transgene displayed increased depression-like
behavior.
Mitochondrial dysfunction is increasingly implicated in
psychiatric disease, however, not all mitochondrial disease
patients develop psychiatric symptoms. What is the biologic
mechanism by which a mitochondrial dysfunction increases
susceptibility to PTSD in a particular individual? Does mito-
chondrial dysfunction play a role in any or all previously
mentioned physiologic processes involved in PTSD patho-
physiology? If SMF plays a role in only some features of
PTSD pathophysiology but not all, why does it play a role in
the particular mechanisms in which it does and not in others?
How does a particular mitochondrial dysfunction in a partic-
ular individual interact with the environment in terms of a
particular traumatic event or set of traumatic events and the
stress response mobilized to contribute to a particular feature
of PTSD pathophysiology to ultimately increase PTSD sus-
ceptibility? Is mitochondrial dysfunction sufficient to increase
susceptibility to PTSD in a patient, or is it one aspect in a
multi-hit disease model?
Conclusion
Here we have outlined several potential mechanisms by which
mitochondrial dysfunction or reduced mitochondrial capacity
may increase susceptibility to PTSD or exacerbate PTSD
symptomatology. Specifically, inability to efficiently affect
critical inhibitory neural circuits or affect long-term potentia-
tion through bioenergetic- and Ca2+ homeostasis-sensitive
GABA-ergic neurons, disrupted neurogenesis, cell
592
remodeling, and apoptosis in response to stress signaling, ex-
cessive or imbalanced pro-inflammatory signaling secondary
to inappropriate ROS production, and an inability to maintain
appropriate synthesis of glucocorticoid hormones, may singu-
larly, or in concert, affect PTSD disease etiology. However,
much research is still required to elucidate whether any or all
of these mechanisms contribute to PTSD vulnerability in pa-
tients, how these individual mechanisms interact within a par-
ticular individual, with a particular mitochondrial dysfunction,
and in response to a particular traumatic event exposure, and
whether those particular interactions reveal biomarkers for
identifying susceptible patients, or personalized strategies for
treatment and/or prevention.
Funding No funding was provided for this work.
Compliance with ethical standards
Conflict of interest None.
No IACUC approval was required for this work.
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