Biochimica et Biophysica Acta 1863 (2017) 1090–1097

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Invited review

Mitochondria as a centrally positioned hub in the innate

immune response☆
Rajat Sandhir ⁎, Avishek Halder, Aditya Sunkaria
Department of Biochemistry, Panjab University, Chandigarh, India

a r t i c l e i n f o a b s t r a c t

Article history: Mitochondria are vital organelles involved in numerous cellular functions ranging from energy metabolism to
Received 5 September 2016 cell survival. Emerging evidence suggests that mitochondria provide a platform for signaling pathways involved
Received in revised form 21 October 2016 in innate immune response. Mitochondrial ROS (mtROS) production, mitochondrial DNA (mtDNA) release,
Accepted 22 October 2016
mitochondrial antiviral signaling protein (MAVS) are key triggers in the activation of innate immune response
Available online 26 October 2016
following variety of stress signals that include infection, tissue damage and metabolic dysregulation. The process
Keywords:
is mediated through pattern recognition receptors (PRRs) that consist of retinoic acid inducible gene like
Inflammasome: innate immune response receptors (RLRs), c-type lectin receptors (CLRs), toll type receptors (TLRs) and nuclear oligomerization-domain
Inflammation like receptors (NLRs). These signals converge to form a multiprotein complex called inflammasome that leads
Mitochondria to caspase-1 activation to promote processing of precursor cytokines (pro-IL1β and pro-IL-18) to active cytokines
NLRP3 (IL-1β and IL-18). It appears that mitochondria induced inflammasome activation contributes to inflammatory
process in many diverse disorders. Therefore, strategies aimed at modulating mitochondria mediated
inflammasome activation might be beneficial in many pathophysiological conditions. This article is part of a Spe-
cial Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of
Diseases - edited by P. Hemachandra Reddy.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction that a number of mitochondrial components interact with or activate

NLRP3 inflammosome that is the key effecter in the innate immune
Mitochondria are dynamic organelles involved in wide range of cel- response [5].
lular functions that include bioenergetics, metabolism and programmed Mitochondrial dysfunctions are considered crucial for NLRP3
cell death [1]. Recently, it has been shown that the mitochondria are inflammasome activation partly through the release of toxic products,
major players in the innate immune response in antimicrobial defense such as mitochondrial reactive oxygen species (mROS) and mitochon-
and sterile inflammation [2]. Mitochondria are active participants in a drial DNA (mtDNA). mROS is a key signal in NLRP3 inflammasome
broad range of innate immune responses, where they not only provides activation. It has been observed that inhibition of mitochondrial com-
a platform for various signaling events but also contributes to the effec- plex I by rotenone and complex II by antimycin A induces robust ROS
tor response [2]. The role of mitochondria in inflammation was initially production from mitochondria that activates NLRP3 inflammasome
suggested from studies that identified mitochondrial antiviral signaling [6]. Furthermore, it has been demonstrated that inhibition of the mito-
protein (MAVS) in eliciting antiviral interferon response during viral in- chondrial voltage-dependent anion channel (VDAC) suppresses both
fection [3]. Mitochondria have been involved in inflammatory cell death intracellular ROS generation and inflammasome activation suggesting
termed as ‘pyroptosis’ that is mediated through activation of Nod-like that the mROS production directly regulates NLRP3 inflammasome [7].
receptor family, pyrin domain containing 3 (NLRP3) inflammasome. mtDNA released from the mitochondrial matrix into the cytoplasm
The discovery of the NLRP3 inflammasome and pyroptotic cell death has also been shown to directly contribute to NLRP3 inflammasome ac-
in the last decade has demonstrated the involvement of mitochondria tivation [8]. It has been observed that oxidized mtDNA directly activates
as key players in the inflammatory response [4]. Evidence suggests NLRP3 inflammasome and this interaction is competitively inhibited by
oxidized dG (8-OH dG). Recent studies have shown that mitochondrial
dynamics also plays a critical role in the innate immune response by
☆ This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial
influencing NLRP3 inflammasome activity [9]
Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P.
Hemachandra Reddy.
Numerous studies have demonstrated that mitochondrial events are
⁎ Corresponding author. associated with NLRP3 activation in disease conditions like Alzheimer's
E-mail address: sandhir@[Link] (R. Sandhir). disease (AD), Parkinson's disease (PD), type 2 diabetes, atherosclerosis

[Link]
0925-4439/© 2016 Elsevier B.V. All rights reserved.
 R. Sandhir et al. / Biochimica et Biophysica Acta 1863 (2017) 1090–1097 1091

[10], gout, renal injury and cancer [11]. Mitochondrial dysfunction acts NF-κB and JNK. This activation rapidly increases the transcription of pro-
upstream of NLRP3 activation by providing triggers for such activation inflammatory factors like NLRP3 and pro-IL-1β [25,26]. A significant
in the pathological processes [12]. Mitochondrial events also act down- increase in the transcription of both NLRP-3 and pro-IL-1β is required
stream to NLRP3 activation. It is evident that mitochondria and NLRP3 for the formation of functional inflammasome, as these are weakly
inflammasome machinery are closely interwoven at multiple levels. expressed under basal conditions. On the other hand, ASC and pro-
Therefore, therapeutics that target mitochondria mediated NLRP3 caspase-1 are highly expressed in the cytoplasm. Thereafter, pro-
inflammasome activation may hold great promise in the treatment of caspase-1 is auto-catalytically cleaved (after binding to the NLRP3
diverse disease conditions. inflammasome complex) to form active caspase-1 that converts pro IL-
1β and IL-18 to their active forms [27–29]. It is now an established fact
1.1. Innate immune response and inflammosome activation that a number of mitochondrial factors play crucial roles in the NLRP3
pathway. The activation of NLRP-3 can be classified as canonical (IL-1β
The innate immune response is an evolutionary conserved compo- and IL-18 dependent) and noncanonical (tumor growth factor β depen-
nent of immune system that acts as a first line of defense against harm- dent) [30]. The NF-κB mediated activation falls under the noncanonical
ful stimuli [13]. Innate immune response is activated by intracellular or category, whereas, triggering of NLRP-3 activity by ROS is catego-
surface-expressed pattern recognition receptors (PRRs) present on in- rized as canonical activation.
flammatory cells like macrophages, neutrophils, dendritic cells and mi-
croglia [14]. These receptors detect pathogen-associated molecular 1.3. Mitochondria and inflammasome activation
patterns (PAMPs), such as microbial nucleic acids, lipoproteins, carbo-
hydrates, or damage-associated molecular patterns (DAMPs) released Mitochondria are vital to many cellular functions that include main-
from injured cells. PAMPs and DAMPs initiate an intricate set of signal- tenance of the balance between biogenesis and biosynthesis. These two
ing interactions releasing pro-inflammatory cytokines (IL-1β and IL-18) functions are in direct control of signals coming from and to the nucleus.
that prompt inflammatory response [15]. PRRs like membrane-bound Mitochondria transduce signals in many different ways. It has been well
receptors such as Toll-like receptors (TLRs), interleukin receptors known that mitochondria contain numerous unique proteins which are
(ILRs), and tumor necrosis factor receptor 1 (TNF-R1) and 2 (TNF-R2) encoded in the nucleus and transported to mitochondria [31]. In addi-
are involved in the activation of innate immune response. PRRs on rec- tion, many enzymes from tricarboxylic acid (TCA) cycle and electron
ognizing their respective extracellular ligands initiate intracellular sig- transport chain (ETC) are involved in the influx of calcium to mitochon-
naling events like (i) activation of NF-κB, a transcription factor which dria from cytosol, which is an example of anterograde (nuclear to
up-regulates expression of a wide variety of stress-response genes or mitochondria) signal transduction [32]. The regulation of hypoxia
through (ii) post-translational modification, which involves activation inducible factor-1 (HIF-1) activation by ROS is an example of retrograde
of c-Jun amino-terminal kinase (JNK) [16]. Moreover, there are intracel- (mitochondria to nucleus) signaling [33]. Impaired ETC function results
lular PRRs that recognize inflammatory ligands in the cytosol and inter- in decreased ATP production and thereby increasing AMP concentra-
act with a variety of associated factors to form large cytoplasmic tion. This results in a shift from anabolic to catabolic state to maintain
assemblies that activate caspase-1 which ultimately converts pro- high ATP/ADP ratio [34]. Increased AMP levels induce AMP-activated
inflammatory cytokines (pro IL-1β and pro IL-18) to their active form protein kinase (AMPK) activity which subsequently deceases the
[17]. Cytoplasmic PRRs, like nucleotide-binding domain leucine-rich activity of mammalian target of rapamycin (mTOR). In addition,
repeat-containing receptors (NLRs), recognize a wide spectrum of intra- production of ROS is also coupled to its metabolism. The production of
cellular inflammatory stimuli. There are four classes of NLRs (NLRP1, ROS is not a random process but is a consequence of a number of very
NLRP3, NLRC4 and AIM2) that sense a variety of inflammatory signals intricately regulated pathways like NFκB and JNK signaling [35]. In
to mediate caspase-dependent activation of cytokines [18]. Among mitochondria, the availability of TCA cycle intermediates (like acetyl-
these, NLRP3 is the most extensively studied and its activation is CoA, succinate, fumarate, and α-ketoglutarate) and its enzymes have
triggered by a variety of stimuli, including infection, tissue damage profound effect on further downstream signaling [36,37]. For instance,
and metabolic dysregulations. NLRP3 inflammasomes are complex reduction in α-ketoglutarate dehydrogenase complex (KGDHC) activity
association of cytosolic NLRP3, ASC, and caspase-1 in macrophages appear to be a common feature of neurodegeneration in various condi-
[14]. Membrane-bound PRR signals aid in activating the NLRP3 tions like AD [38–40], PD [41] and Huntington's disease [42,43]. It is
inflammasome via mROS [19] or specific interaction with mtDNA [20], worth mentioning that severity of dementia varies positively with
cardiolipin [21], or MAVS [22] and disturb the homeostasis of mitochon- KGDHC reduction whereas there may or may not be any APOE4 allele
drial bioenergetics and biosynthetic status. Activation of inflammasome in the patients [44]. Moreover, Aβ has shown to be localized in mito-
results in cleavage of pro-IL-1β and pro-IL-18 to their active forms that chondria where it reduces KGDHC and pyruvate dehydrogenase com-
are secreted from the cell to spread inflammation. The NLRP3 plex (PDHC) activities [45]. These findings suggest that metabolic
inflammasome is associated with onset and progression of various dis- enzymes play an important role in the pathogenesis of various neurode-
eases, including metabolic disorders, multiple sclerosis, inflammatory generative diseases and links the brain innate immune system to
bowel disease, as well as other inflammatory diseases [23]. mitochondria.
TCA intermediates and enzymes play a critical role in development
1.2. NLRP3 inflammasome activation of abnormalities associated with various physiological disorders. It has
been observed that succinate and citrate participate in LPS induced
NLRP3 is a complex of NACHT (NAIP, neuronal apoptosis inhibitor inflammatory cytokine synthesis. Succinate has been observed to inhibit
protein; C2TA, class 2 transcription activator of the MHC; HET-E, prolyl hydroxylase (PHD) and increase the stability of HIF-1α and
heterokaryon incompatibility, and TP1, telomerase-associated protein 1); pro-inflammatory cytokines [46]. In addition, succinate is found to
LRR, leucine-rich repeat, and PYD, PYRIN domain. This complex is one of increase mROS production by reversing the electron transport through
the major factors involved in the activation of caspase-1. The binding of complex-I of ETC. Studies have shown that mitochondria play an
NLRP3 with ASC adaptor protein (apoptosis-associated speck-like protein) important role in innate immune response mediated by mROS produc-
containing a CARD domain (caspase recruitment domain) allows the re- tion [47]. Activation of TLR4 and subsequent translocation of TNF
cruitment of pro caspase-1. The dimerized form of ASC associates with receptor associated factor 6 (TRAF6) to mitochondria increases mROS
pro-caspase-1 leading to formation of NLRP3 inflammasome in macro- production. Moreover, TRAF6 interact with evolutionarily conserved
phages [24]. As soon as specific signals are received the membrane signaling intermediate in Toll pathways (ECSIT) which forms a part of
bound PRRs like TLRs, ILRs, TNFRs activates the transcription factors like complex-I in ETC [48]. Other PRRs like NLRs also depends on mROS
1092 R. Sandhir et al. / Biochimica et Biophysica Acta 1863 (2017) 1090–1097

production. Decreased mROS production has been correlated with TRAF molecules can be recruited without proline rich repeats in the
diminished levels of NLRP3 inflammasome activation. Blockade of dimerized CARD domains of MAVS. In TLR signaling both myeloid differ-
autophagy and permeabilization of lysosomal membrane are conse- entiation primary response protein 88 (MYD88) dependent and TIR-
quence of high mROS, which ultimately is responsible for NLRP3 domain-containing adaptor protein inducing IFNβ (TRIF) dependent
inflammasome activation [7,49]. Moreover, studies indicate that the re- signaling have been observed. However, TNFR1 pathway is mediated
lease of oxidized mtDNA is involved in the activation of NLRP3 through the interaction of TNFR1-associated death domain protein
inflammasome [8]. It has been shown that calcium influx and potassium (TRADD) with MAVS. This TRADD-MAVS complex can recruit TRAF3
efflux disrupt mitochondrial membrane which could be a probable and TANK (TRAF family member-associated NFκB activator). This bind-
cause of mtDNA release and increase in mitochondrial oxidative ing activate IκB kinase-ε (IKKε) and/or TANK-binding kinase 1 (TBK1),
damage. A range of DAMPS including α-synuclein [50], Aβ [51], prion resulting in activation of IRF3 and IRF7. On the other hand, TRADD-
fibrils [52], and ATP [53] can effectively activate NLRP3. Involvement MAVS can recruit FAS-associated death domain protein (FADD) and
of NLRP3 mediated pathological conditions are observed in traumatic receptor-interacting protein 1 (RIP1) inducing canonical NFκB signaling
brain injury [54], bacterial meningitis [55], viral encephalitis [56] and [70].
AD [57]. Studies on mouse model of AD have revealed that down
regulation of NLRP3 inflammasome skew microglial cells toward M2 1.5. Mitochondrial dynamics and innate immune response
phenotype with increased capacity of Aβ clearance. Moreover, increase
in NLRP3 inflammasome activity are also associated with a number of Mitochondrial dynamics has recently been shown to be a key
dominant inherited diseases like cryopyrin associated period syn- regulator of NLRP3 inflammasome pathway [9]. Studies showed
dromes (CAPS), composed of Muckle–Wells syndrome (MWS), familial knockdown of dynamin-related protein 1 (Drp1) resulted in aberrant
cold autoinflammatory syndrome (FACS) and chronic infantile cutane- mitochondrial elongation marked increase in NLRP3-dependent
ous neurological articular syndrome (CINCA) [58]. caspase-1 activation and IL-1β secretion in mouse bone marrow-
Mitochondrial outer membrane can serve as platform for the derived macrophages. In addition chemical inducer of mitochondrial
activation of innate immune response. Retinoic acid-inducible protein fission, like carbonyl cyanide m-chlorophenyl hydrazone clearly attenu-
I (RIG-I)-like receptor family belong to that class of PRRs which ated NLRP3 inflammasome assembly and activation [9]. Further, it has
responds to viral infections. RLRs are known to mediate a critical role been shown that mitofusin 2, a mediator of mitochondrial fusion is
in sensing RNA virus invasion which is composed of three helicases involved in NLRP3 inflammasome activation [71]. Recently, SESN2
namely RIG-I (also known as DDX58), melanoma differentiation- (sestrin 2), known as stress-inducible protein has been shown to sub-
associated gene 5 (MDA5) and laboratory of genetics and physiology 2 due prolonged NLRP3 inflammasome activation probably by inducing
(LGP2). RIG-I binds preferentially to ssRNAs phosphorylated at the 5' mitophagy that removes the damaged mitochondria [72]. Therefore,
end, whereas MDA5 recognizes long dsRNAs without the need for 5' understanding the molecular basis of mitochondrial dynamics is crucial
phosphorylation and LGP2 is thought to be a negative regulator [59]. for establishing a firm connection between mitochondria and innate im-
Structurally RIG-I and MDA5 both have a helicase domain and a mune response.
N terminal caspase recruitment domain (CARD) for downstream signal- It has been shown that activation of MAVS is intricately dependent
ing via adaptor protein located on the mitochondrial outer membrane on the mitochondrial dynamics. In fact, mitofusin-2 (MFN2) interacts
known as mitochondrial antiviral signaling protein (MAVS) or IFN-β with MAVS via a central 4,3 hydrophobic heptad region (HR1) which
promoter stimulator 1 (IPS-1), virus induced signaling adaptor (VISA) results in inhibition of RLR pathways. The loss of endogenous MFN2
and CARD adaptor inducing IFN-β [60,61]. (or reduction in mitochondrial fusion) increases production of IFN-β
followed by a viral infection which leads to decrease in the viral load.
1.4. Mitochondrial antiviral signaling protein (MAVS) and signaling cascade It is thought that MFN2 inhibits the dimerization at the CARD domain
of MAVSs [73]. Mitochondrial elongation is suggested to be a marker
MAVS, a 540 amino acid protein composed of three functional for antiviral activity after specific retinoic acid inducible gene I
domains i) N-terminal CARD domain, ii) a proline rich region and iii) a like helicase (RLH) activation. Under normal conditions mitofusin-1
trans-membrane C terminal domain. The CARD domain of MAVS inter- (MFN1) interacts with MAVS. Moreover, MAVS interacts with stimula-
acts with the CARD domain of RIG-I and MDA5 which activates the tor of interferon genes (STING), molecule in endoplasmic reticulum
downstream pro-inflammatory cytokines via NF-κB and IRF pathway involved in antiviral cell response. This suggests a role of mitochondrial
[62–66]. The proline rich region also interacts with TRAF and thus can fusion in cellular antiviral response. Activation of RLH induces the
also transduce the signal downstream but TRAF can interact with consequent breakdown of MAVS-MFN1-STING complex, located at
MAVS lacking the proline rich region indicating that it may interact ER-mitochondrial junctions. The released MFN1 plays its role in
with other regions in MAVS [61,67]. Absence of C terminal transmem- mitochondrial elongation while the broken down complex enhances
brane domain localizes the protein to the cytosol which again will inhib- the STING-MAVS downstream signaling [74]. It has been reported that
it the signal transduction process. The C terminal domain of MAVS has MFN1 mediate mitochondrial fusion and regulate RIG-I signaling to sup-
shown similarities with transmembrane domain of tail anchored pro- press dengue virus (DENV) replication. Moreover, MFN2 has a role in
teins of mitochondria, including various Bcl-2 family proteins [68]. providing protection against DENV by maintaining mitochondrial mem-
Thus, indicating that outer mitochondrial membrane targeting is re- brane potential (MMP). Yu et al. have shown that DENV protease NS2B3
quired for the proper signal transduction. In addition, the transmem- could cleave MFN1 and MFN2, resulting in the suppression of mitochon-
brane domain provides a site for dimerization of MAVS which is drial fusion as well as modulating the interferon production to promote
important for TRAF binding. The activation of NF-κB and IRF (IRF3 and infection [75]. Mitochondrial Rho GTPase (Miro1 and Miro2) have
IRF7) pathways following MAVS signaling is a matter of intensive re- shown to modulate the mitochondrial dynamics. VopE, a GTPase acti-
search. Many innate immune signaling molecules are involved down- vating protein, localizes to mitochondria during V. cholerae infection
stream of MAVS. A number of TRAF family members TRAF 2, 3 and 6 and interfere with the functioning of Miro1 and Miro2 to block host in-
interact with proline rich region of MAVS via its TRAF interacting nate immune response [76].
motif [61,67]. TRAF 3 and TRAF 5 associate with dimerized CARD In neurodegenerative diseases accumulation of misfolded protein
domain of MAVS [69]. Interestingly, requirement of proline rich repeats results in aggregation of their native counterparts through a mechanism
in MAVS for the recruitment of TRAF induced dimerization of CARD similar to pathogenic induction of prion proteins. MAVS like prions
domain can be substituted or complemented with higher expression share the ability to infect the endogenous protein and convert it into
of MAVS defective in proline rich repeats. Thus, suggesting that the aggregate forms or formation of fiber-like polymers and resistance
 R. Sandhir et al. / Biochimica et Biophysica Acta 1863 (2017) 1090–1097 1093

to protease digestion as well as solubilization by detergent. In addition, disorders like AD, PD, alcohol use disorders, depression, bipolar disorder
disulfide linkages have been observed in functional MAVS aggregates and even intracellular hemorrhage have shown to be the result of aggra-
[77]. However, the disulfide bonds are not essential for the maintenance vated levels of immune response with direct or indirect involvement of
of MAVS aggregates and their activity. It would be interesting to study mitochondria. Recently, it has been demonstrated that obesity could
the role of mitochondria and innate immune mediators in resolving accelerate endothelial dysfunction in Otsuka Long-Evans Tokushima
these aggregates in neurodegenerative diseases. The changes in NLRP3 Fatty rats via the activation of NLRP3 and mitochondrial dysfunction
response following clearance of such aggregates on brain is a matter [97]. Most notably, involvement of mitochondrial uncoupling protein 2
of further study. Recent reports suggest that MAVS aggregates are (UCP2) has been found to negatively regulate NLRP3 activation in depres-
degraded by ubiquitin-proteasome pathways. However, mitophagy sion [98]. Ethanol was also reported to activate innate immune response
may be involved in proper clearance of such aggregates. by TLRs and NLRP3 inflammasome, probably by elevating the mROS pro-
Different physiological conditions induce different levels of hormone duction [99]. Moreover, studies involving long term neurodegenerative
receptors and this in fact regulates the effectiveness of these hormones disorder like AD have shown increased mROS production and subsequent
in regulating the mitochondrial balance. Thyroid hormones, T3 and T4 activation of NLRP3 [100]. Recently, Zhong et al. have shown increased
have been found to maintain the number and mass of mitochondria in levels of p62, a mitophagy signal, after recruitment and phosphorylation
both liver and cardiac tissues. Moreover, T3 was found to elevate of PARKIN in PD model probably via NFκB mediated signaling [101]. In ad-
mitochondrial biogenesis in oxidative (slow twitching) muscles but dition, rotenone was found to induce NLRP3 priming in response to high
not in glycolytic (fast twitching) muscles [78]. Thus, exploring the effect grade mROS generation [12]. Disorders like intracerebral hemorrhage
of innate immune response on mitochondrial dynamics could provide a [102] and bipolar disorder [103] are also attributed to increase in mROS
better insight into the progression of the diseases. mediated NLRP3 activation. Moreover, complex-I dysfunctioning has
also found to be positively correlated with NLRP3 activation in bipolar dis-
1.6. Mitochondria mediated activation of immune response in order. Relationship between mitochondria and innate immune response
neurodegenerative disorders in various neurodegenerative disorders has been summarized in
Table 1. The network involved in controlling the stages and complexities
Central nervous system (CNS) lacks parenchymal dendritic cells and of these disorders varies on the extent of damage on mitochondrial and
therefore becomes vulnerable to chronic and latent infections [79]. immune homeostasis. Extensive research is required to understand the
However, it may be a strategy to save delicate, non-regenerating post molecular events involved during the post translational modifications
mitotic cells like neuron and oligodendrocytes from robust inflamma- which govern the progression of mitochondria mediated immune
tion after adaptive response. The blood brain barrier (BBB) precisely response.
excludes plasma proteins as well as peripherally derived innate and
adaptive immune cells and their associated inflammatory molecules 1.7. Targeting mitochondria mediated innate immune response
[80]. Therefore, the basic host defense mechanism is operational in mi-
croglia and astrocytes, which deals directly with pathogen or damage Mitochondria are not only energy providing machinery but a cohort
associated stress. Microglia, the resident monocytes of the brain is a of different biological machines working in a synchronized manner to
unique myeloid cell population that develops from yolk sac before maintain cellular homeostasis. Even a small asynchrony in this delicate
vascularization or definitive hematopoiesis in the embryo [81]. Once balance could leads to various anomalies like disturbance in membrane
established in the CNS parenchyma they can proliferate from resident potential, imbalance in TCA intermediates, mtDNA associated damage,
progenitors to maintain its sustainability [82]. Similar to resident
macrophages in the body, microglia also maintain two types of popula- Table 1
tion in the brain (M1 - inflammatory and M2 - anti-inflammatory). Relationship of mitochondria and innate immune response in neurodegenerative
Microglial activation is a major problem in numerous neurodegenerative disorders.
conditions. Chronic neurodegeneration or systemic challenges like Neurodegenerative Role of mitochondria and immune References
stroke or physical trauma induce activation of microglia have been disorders response
reported to elicit cytokine response [83–87]. Moreover, microglias have
Depression Mitochondrial uncoupling protein 2 [98]
shown to be directly activated by Aβ molecules through NALP3 (UCP2) negatively regulates NLRP3
inflammasome pathway [51]. Glial cells are derived from neuroepithelial activation
stem cells and divided into astrocytes, oligodendrocytes, and Alcohol use disorder Ethanol activates innate immune [99]
polydendrocytes. Glial cells provide functional support to the neurons (AUD) response by TLRs and NLRP3
inflammasome, mainly through mROS
and helps in maintaining synaptic plasticity [88–92]. Astrocytes are the generation.
glial subpopulation that also involved in the innate responses of the Parkinson's disease α-Synuclein aggregation induces [50]
brain, mediated by activation of TLR and NLR signals. Interaction (PD) inflammatory response through TLR2
between microglia-astrocyte is critical in CNS innate immunity [93]. and NLRP3 activation in human
primary monocytes.
In recent years, involvement of NLRP-3 has been studied in
Rotenone induces priming of NLRP3 in [12]
progression of CNS diseases like multiple sclerosis (MS), a demyelin- response to high grade mROS.
ating inflammatory disease, AD [57,58] and PD [94,95]. In MS and AD, Accumulation of PINK-1 in the outer [101]
deactivation of inflammasome complex has shown to be protective membrane of mitochondria recruits
in nature. Accumulation of protein aggregates like Lewy bodies, PARKIN that further activates it by
phosphorylation. This serves as a “eat
senile plaques, or PrPsc can stimulate the activity of inflammasome me” signal by mitochondria marked by
induced production of pro-inflammatory cytokines in microglial adaptor protein p62. Zhong et al.
cells [96]. Though, not much is known about their cross talk at the showed increase in level of p62 in PD
molecular level but inhibitors of NLRP-3 inflammasome has already model probably via NFκB mediated
signaling.
shown the promise for developing interesting therapeutics.
Bipolar disorder Increase in NLRP3, ASC following [103]
A number of neurodegenerative disorders are attributed to (BD) complex-I dysfunction
deregulated cross talk between the main energy producing center Alzheimer's disease Increased mROS production and [100]
of the cell and initiation of the immune response. Most of the intermedi- (AD) concomitant activation of NLRP3
ates involved in the signaling cascades were extensively studied in neuro- Intracellular mROS triggers NLRP3 inflammasome [102]
hemorrhage activation
pathologies, cardiovascular and renal disorders. Neurodegenerative
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production of mROS, and maintenance of cellular life or death via VDAC scavenging and enhanced ETC function [112]. CoQ10, a natural antioxi-
expression. All these processes directly or indirectly influence the im- dant which acts as a mobile electron carrier between complexes I and
mune response of a cell which further manifests the consequence of III or complexes II and III, can impede brain mitochondrial dysfunctions
various disorders. A number of strategies have been implemented in induced by Aβ neurotoxic amino acid sequences. Cyclosporine A is also
maintenance of mitochondrial homeostasis. Lithium chloride, an effective in counteracting the adverse effects of Aβ neurotoxicity on
inhibitor of GSK3β, treatment has shown to prevent hippocampal brain mitochondria [113]. Studies on chloroquinol, an antimalarial
neuronal apoptosis induction after radiation exposure [104]. GSK3β drug, showed their effectiveness in reducing calcium accumulation
phosphorylates VDAC which hinders the binding of hexokinase II with and oxidative stress, thus ameliorating the AD symptoms [114]. These
mitochondrial outer membrane and mediate apoptotic induction. therapies and the signaling cascades have paved a path toward a new
Natural and artificial uncouplers (UCPs) like fatty acids, proteins, and horizon where mitochondria are visualized as hub in a network where
carbonyl cyanide m-chlorophenylhydrazone (CCCP) have shown to it receive signals, process them and initiate the steps in the innate
decrease membrane potential and thus could reduce mROS [105]. immune response.
UCPs play an important role in the pathogenesis of numerous disorders
including obesity, type-2 diabetes [106], aging and tumor progression
[107]. Various mutations in mtDNA are believed to be responsible for 2. Conclusions
nearly 120 syndromes involving mitochondrial proteins [108].
Recently, Wiens and Ernst have shown that treating macrophages Mitochondria are emerging as key scaffolds in the innate immune
with mitochondria specific MitoQ reduced cytosolic mtDNA and response against microbial pathogens and during sterile insults. The
inhibited IFNβ induction by Mycobacterium tuberculosis [109]. Selective innate immune response is triggered by ROS and mtDNA that leak
blocking of mutant mtDNA replication by peptide nucleic acid, in order from the damaged mitochondria. These triggers result in the assembly
to promote wild type mtDNA could be a potent remedy for such of multimeric protein complex “inflammasome” that leads to
disorders [110]. Scavenging mROS has also shown to be a potential generation of active caspase-1 that cleaves the precursor cytokines
strategy adopted for treatment in mitochondria related disorders like (pro-IL-1β & pro-IL-18) to biologically active cytokines (IL-1β &
AD, PD, amyotrophic lateral sclerosis (ALS). Ubiquinol and its pharma- IL-18) that induces inflammatory form of cell death known
cologically manipulated derivatives are found to be highly effective in as ‘pyroptosis’ (Fig. 1). Mitochondrial dysfunctions leading to
decreasing damages associated with mitochondria associated nitration activation of innate response has been implicated in diverse patho-
[111]. NO scavengers like cPTIO (partial inhibitor of complex I) and logical conditions. Therefore, modulation of mitochondria mediated
FeTPPS and MnTBAP (complete blockers of complex I) have been effec- inflammasome activation may provide a new therapeutic strategy in
tive in experimental stages. In addition, MitoQ10 and MitoVit E (homo- disease conditions with altered pathogenic axis involving mitochondria
logues of ubiquinone and vitamin E respectively) showed more ROS and inflammation. However, further studies will be required to

Fig. 1. Mitochondria mediated signaling events involved in the innate immune response. Mitochondria function as a center for exchange of various signals involved in the innate immune
response. Damage associated molecular patterns (DAMPs) like α-synuclein, amyloid β (Aβ), prion fibrils, adenosine triphosphate have shown considerable ability to activate NLRP3
inflammasome. In addition, mitochondrial reactive oxygen species (mROS), mitochondrial antiviral signaling protein (MAVS) and intracellular calcium are also involved in activating
NLRP3 inflammasome. TCA cycle intermediates like succinic acid induce expression of pro-inflammatory cytokine. mtDNA is also contributes to increased pro-inflammatory cytokine
synthesis via TLR pathways. DAMPs like Aβ impede metabolic control by reduction in activity of α-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase
complex (PDHC). These mitochondrial triggers induce NLRP3 inflammasome that through activation of caspase-1 converts pro-inflammatory cytokines to their bioactive form (IL-1β
and IL-18) leading to pyroptosis.
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identify strategies to modulate inflammosome activation in beneficial [23] B.Z. Shao, Z.Q. Xu, B.Z. Han, D.F. Su, C. Liu, NLRP3 inflammasome and its inhibitors:
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