Mitochondria in innate immunity.

Abstract

Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.

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Mitochondria are cellular organelles involved in host-cell meta-
bolic processes and the control of programmed cell death. A direct
link between mitochondria and innate immune signalling was first
highlighted with the identification of MAVS—a crucial adaptor for
RIGI-like receptor signalling—as a mitochondria-anchored protein.
Recently, other innate immune molecules, such as NLRX1, TRAF6,
NLRP3 and IRGM have been functionally associated with mitochon-
dria. Furthermore, mitochondrial alarmins—such as mitochondrial
DNA and formyl peptides—can be released by damaged mitochon-
dria and trigger inflammation. Therefore, mitochondria emerge as a
fundamental hub for innate immune signalling.
Keywords: mitochondria; innate immunity; MaVS; pathogen;
host metabolism
EMBO reports (2011) 12, 901–910. doi:10.1038/embor.2011.157
See glossary for abbreviations used in this article.
Introduction
innate immune responses in mammalian cells rely on the detec-
tion of conserved molecular motifs found in microbial pathogens
and known as ‘pathogen-associated molecular patterns (paMps)’,
which include viral nucleic acids as well as bacterial molecules
such as lipopolysaccharide, lipoproteins, flagellin, peptido glycan
and cpg Dna (Medzhitov, 2007). in the past few years, it has also
become clear that non-microbial danger signals—composed of
host mol ecules often released by necrotic cells in the context of tis-
sue damage and known as ‘danger-associated molecular patterns
(DaMps)’—also trigger innate immune signalling and promote
inflammation (Benko et al, 2008). Both paMps and DaMps trig-
ger innate immunity following detection by several families of host
sensor molecules, collectively called pattern recognition recep-
tors (prrs). the most-studied families of mammalian prrs include
toll-like receptors (tlrs; akira & takeda, 2004), nod-like receptors
(nlrs; Fritz et al, 2006) and rigi-like receptors (rlrs; takeuchi &
akira, 2009). tlrs are membrane-spanning molecules that detect
extracellular or luminal paMps and DaMps, whereas nlrs and
rlrs sense intra cellular molecular signatures. once activated, prrs
trigger specific host defence signalling, the most commonly studied
of which are pro-inflammatory pathways that activate nuclear fac-
tor κB (nF-κB), in response to most tlrs, the nlr family members
noD1 and noD2, and rlrs; caspase 1 inflammasome, activated
by the nlrp subfamily of nlr proteins and rlrs; and type i inter-
feron (Elinav et al, 2011; Kawai & akira, 2011; loo & gale, 2011).
Finally, several new prrs have been identified recently that detect
intracellular foreign Dna, and these include aiM2, iFi16 and zBp1/
DlM1 (Barber, 2011).
With regards to the mechanisms that underlie prr activation, a
key remaining question is whether MaMp and DaMp detection is
a direct ligand–receptor interaction or whether it requires multiple
cofactors and complex modifications of host metabolic and homeo-
static functions. in support of the latter hypothesis, numerous lines of
evidence have recently highlighted the importance of mitochondria
and mitochondrial functions in the regulation of host innate immune
signalling. importantly, although this organelle seems to be a signal-
ling hub for innate immunity, there is strong compelling evidence to
show that not only do mitochondria provide a molecular platform
for signalling, but also that innate immunity and basic mitochon-
drial functions are integrated. therefore, an emerging concept is that
innate immune signalling is under the functional check of basic host
metabolic functions, such as oxygen consumption, atp production
and possibly biosynthetic pathways that depend on mitochondrial
activity and fitness.
PAMP detection and glycolytic switch
the main source of energy in the cell is the atp that is generated
through mitochondrial oxidative phosphorylation or through glyco-
lysis. oxidative phosphorylation is active in the presence of oxygen,
whereas glycolysis is favoured under anaerobic conditions. the
switch towards glycolytic atp has recently been implicated in the
activation and maturation of murine dendritic cells ( Jantsch et al,
2008; Krawczyk et al, 2010). Dendritic cells stimulated with various
tlr agonists have increased lactate production, higher expression
of glucose transporter 1 and decreased oxygen consumption, all of
which are signals of glycolytic metabolism (Krawczyk et al, 2010).
importantly, lpS-induced glycolysis is dependent on the pi3K/aKt
pathway and could be negatively regulated by the anti- inflammatory
cytokine il-10 or aMp-activated protein kinase, a key regulator
of oxidative phosphorylation (Krawczyk et al, 2010). in addition,
macrophages are also highly dependent on glycolysis for atp pro-
duction, which is elicited by the transcription factor HiF1α—a key
regulator of hypoxia (cramer et al, 2003). although a rapid increase
Mitochondria in innate immunity
Damien Arnoult1, Fraser Soares2, Ivan Tattoli2 & Stephen E. Girardin2*
1INSERM U1014, Hopital Paul Brousse, Batiment Lavoisier, Villejuif, France, and 2Department of Laboratory Medicine
and Pathobiology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
1INSERM U1014, Hopital Paul Brousse, Batiment Lavoisier, 14 avenue Paul Vaillant
Couturier, 94807 Villejuif Cedex, France
2Department of Laboratory Medicine and Pathobiology, Medical Sciences Building,
University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada
*Corresponding author: Tel: + 416 978 7507; Fax: +416 978 5959;
E-mail: stephen.girardin@utoronto.ca
Received 6 June 2011; accepted 10 July 2011; published online 29 July 2011

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in atp through glycolysis is important for macrophage function,
there is evidence to suggest that glycolysis can also be a protective
mechanism against inflammatory stimuli (garedew et al, 2010). lpS
and iFnγ stimulation normally result in nitric-oxide-dependent mito-
chondrial dysfunction, leading to a collapse of the mitochondrial
membrane potential (ΔΨm) and apoptosis (garedew et al, 2010).
interestingly, lpS and iFnγ-activated macrophages are less vulner-
able as a result of glycolytic atp production, which can maintain
ΔΨm, thereby preventing cellular apoptosis (garedew et al, 2010).
the regulation of cellular metabolism by switching from oxidative
phosphorylation to glycolysis seems to be critical in the activation
and protection of certain immune cell populations.
Mitochondrial targeting by microbial effectors
Mitochondria are known to control intrinsic apoptotic cell death,
and as host-cell death is a common feature of infected cells, early
reports focused on a possible impact of microbial-derived proteins on
host-cell viability (arnoult et al, 2009a). indeed, several viruses have
been shown to block mitochondria-dependent apoptotic cell death,
including those that encode viral homologues of the anti-apoptotic
protein Bcl2, such as the 19 kDa product of the adenovirus E1B
gene (named E1B-19K) (Degenhardt et al, 2000) or the Epstein–Barr
virus protein BHrF1 (Henderson et al, 1993). other viral proteins,
such as F1l and n1l proteins from vaccinia virus and vMia from
human cytomegalovirus, block apoptosis by interfering with the pro-
apoptotic proteins BaK and BaX at the mitochondrial outer mem-
brane (Kvansakul et al, 2007; Wasilenko et al, 2003). another group
of viruses instead seems to promote host-cell apoptosis as a patho-
genic mechanism. this is the case of the viral protein r of human
immunodeficiency virus 1, which interacts with the mitochondrial
outer membrane protein VDac, resulting in the opening of the
mitochondrial permeability transition pore (mptp), loss of the inner
membrane potential ΔΨm and cytosolic leakage of host apoptogenic
factors ( Jacotot et al, 2000). the hepatitis B virus protein HBx induces
similar mitochondrial collapse after interacting with VDac3, leading
to massive mitochondrial fragmentation and aggregation, and rapid
apoptotic cell death (rahmani et al, 2000; table 1).
Several bacterial effectors also target mitochondria to manipu-
late host-cell death and/or survival pathways. Enteropathogenic
Escherichia coli proteins EspF and Map have amino-terminal mito-
chondrial addressing sequences, and targeting of this organelle
induces ΔΨm loss and cell death (nagai et al, 2005); the specific
host mitochondrial proteins that interact with EspF and Map remain
unknown. in addition, several bacterial toxins target mitochondria
and induce cell death. this is the case of Vaca from Helicobacter
pylori, Staphylococcus aureus α-toxin and Clostridium difficile toxin a
Table 1 | Viral and bacterial effectors that target mitochondria
Anti-
apoptotic
factors
Pro-
apoptotic
factors
References
Viruses
AdenovirusE1B–19k—Degenhardt et al, 2000
Epstein–Barr virusBHRF1— Henderson et al, 1993
Vaccinia virusF1L, N1L—Wasilenko et al, 2003
CytomegalovirusvMIA—Kvansakul et al, 2007
HIV-1— VprJacotot et al, 2000
Hepatitis B virus—HBx Rahmani et al, 2000
Bacteria
Legionella
pneumophila
SdhA —Laguna et al, 2006
Escherichia coli— EspF, MapNagai et al, 2005
Helicobacter pylori—VacA Kozjak-Pavlovic et al,
2008
Staphylococcus aureus—
α-toxinKozjak-Pavlovic et al,
2008
Clostridium difficile— Toxin A
and B
Kozjak-Pavlovic et al,
2008
Glossary
ΔΨm
AIM2
AKT
ASC
ATG
BAK
BAX
BCL2
ECSIT

FPR1
FPRL1
gC1q

HIF1α
IFI16
IFNγ
IKK
IL-10
IRF
IRGM
LPS
MAVS
MDA5
MFN1
MyD88
NAP1
NEMO
NLRX1
NOX2
PCBP2/AIP4

PI3K
PLK1
Poly (I:C)
RIGI
RNF5
ROS
STING
TANK
TBK1
TRAF
TRIF
UQCRC2
VDAC
ZBP1/DLM1
mitochondrial membrane potential
absent in melanoma 2
cellular homologue of v-AKT
apoptosis-associated speck-like protein containing a CARD
autophagy-specific gene
BCL2-antagonist/killer
BCL2-associated X protein
B-cell leukaemia/lymphoma 2
evolutionarily conserved signalling intermediate in Toll
pathway
formyl peptide receptor 1
formyl peptide receptor-like 1
complement component 1, q subcomponent binding
protein
hypoxia inducible factor 1, α-subunit
interferon, γ-inducible protein 16
interferon γ
IκB kinase
interleukin 10
interferon response factor
immunity-related GTPase family M protein
lipopolysaccharide
mitochondria-associated viral sensor
melanoma differentiation associated gene 5
mitofusin 1
myeloid differentiation primary response gene 88
NF-κB-activating kinase-associated protein 1
NF-κB essential modifier
NOD-like receptor family member X1
NADPH oxidase 2
poly(rC) binding protein 2 / atrophin 1 interacting
protein 4
phosphoinositide-3-kinase
polo-like kinase 1
polyinosine-polycytidylic acid
retinoic acid-inducible gene I
RING finger protein 5
reactive oxygen species
stimulator of interferon genes
TRAF family member-associated NF-κB activator
TANK-binding kinase 1
TNF-receptor-associated factor
TIR-domain containing adaptor inducing IFN-β
ubiquinol-cytochrome c reductase core protein II
voltage-dependent anion channel
Z-DNA binding protein 1

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and B (Kozjak-pavlovic et al, 2008). Shigella flexneri also induces cell
death in non-myeloid cells through a mechanism that depends on the
opening of the mptp pore, resulting in ΔΨm loss and necrotic cell
death, but whether this process depends on the injection of a specific
bacterial type iii secretion system effector remains unknown (carneiro
et al, 2009). Finally, Legionella pneumophila effector protein Sdha
promotes survival of the infected cells by counteracting necrotic cell
death as a result of mptp opening (laguna et al, 2006; table 1).
Mitochondrial dynamics and antiviral immunity
on infection, viruses are rapidly detected by the innate immune sys-
tem through several classes of prr, including tlrs and rlrs, which
recognize viral components and directly activate immune cells.
on activation, tlrs recruit adaptor proteins such as MyD88 and
triF, leading to downstream signalling cascades and production
of pro inflammatory cytokines such as type i interferons (iFns) and
chemo kines (akira & takeda, 2004). Viral rna that is synthesized in
the cytoplasm of the cell or that is present in viral genomes already
released into the cells is not accessible to tlr3, tlr7 or tlr8, as these
tlrs detect viral nucleic acids presented on the extracellular or lumi-
nal side of host membranes, such as endosomal compartments (akira
& takeda, 2004). Furthermore, fibroblasts and dendritic cells that
lack MyD88 and triF can produce type i iFn after infection with a
number of viruses, suggesting that the tlr system is not always crucial
for innate immune defences against viral infection (Kato et al, 2005).
a new pathway of tlr-independent responses to viruses was
uncovered with the discovery of rigi, the founding member of the
rlr family (takeuchi & akira, 2010; yoneyama et al, 2004), which
also includes MDa5. these are cytosolic helicases that contain two
carD domains (takeuchi & akira, 2010; yoneyama & Fujita, 2008)
and sense viral rna (yoneyama & Fujita, 2008). Both helicases
acquire atpase activity by binding to their ligands, which is required
to induce the conformational changes that lead to the exposure of
the carDs that are otherwise masked by the carboxy-terminal
regulatory domain. this conformational change is required for a
putative interaction with the carD domain of the mitochondrial
adaptor MaVS (also known as ipS1, cardif or ViSa; Kawai et al,
2005; Meylan et al, 2005; Seth et al, 2005; Xu et al, 2005). MaVS,
P
IKKα
IKKβ
IκBα
IκBα
NF-κB
NEMO
TBK1
NEMO
TAB2
TAB3
P
P
IRF7
IRF7
IRF7
Mitochondrion
ER
Cytosol
Single-stranded
RNA virus
Double-stranded
RNA virus
MAVS
TRAF3
CARD
CARD
CARD
TRAF6
TANK
NAP1
RIGI
MDA5
dsRNA
pppssRNA
P
P
IRF3
IRF3
IRF3
TAK1
IKKε
STING
Fig 1 | Overview of the RIGI-like receptor pathway. Viral RNAs are recognized in the cytosol by the helicases RIGI or MDA5. The amino-termini of RIGI and
MDA5 contain two CARD domains that interact with the CARD domain of the mitochondrial adaptor MAVS. MAVS, after recruitment of transactivators,
induces phosphorylation of IRF3 and IRF7 and NF-κB activation, leading to the production of type I IFNs and pro-inflammatory cytokines, respectively.
dsRNA, double-stranded RNA; ER, endoplasmic reticulum; IκBα, inhibitor of κ light polypeptide gene enhancer in B cells, α; IKKε, IκB kinase; IRF, interferon
response factor; MDA5, melanoma differentiation associated gene 5; NAP, NF-κB-activating kinase-associated protein; NEMO, NF-κB essential modifier; NF-κB,
nuclear factor κB; pppssRNA, 5’ triphosphate single stranded RNA; RIGI, retinoic acid-inducible gene I; STING, stimulator of interferon genes; TAB, TAK1-
associated binding protein; TAK, TGF-β-activated kinase; TANK, TRAF family member-associated NF-κB activator; TBK, TANK-binding kinase; TRAF, TNF-
receptor-associated factor.

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through the recruitment of traF3 and traF6, then activates two
cytosolic protein kinase complexes: the ’non-canonical’ iKK-related
kinase tBK1 or iKK-i/e associated with various adaptor proteins,
such as tanK, nap1 and nEMo; or one comprising iKKα, iKKβ
and nEMo (takeuchi & akira, 2010). the tBK1 complex induces
the phosphorylation and dimerization of the transcription factors
irF3 and irF7, which translocate to the nucleus and bind to iFn-
stimulated response elements (iSrEs), thereby resulting in the expres-
sion of type i iFn genes and a set of iFn-inducible genes. the iKK
complex activates nF-κB, subsequently promoting the expression of
pro-inflammatory cytokines (takeuchi & akira, 2010; Fig 1).
the failure of MaVS-deficient mice to mount a proper iFn
response to poly(i:c) stimulation and their severely compromised
immune defence against infections with rna viruses are evidence for
the essential role of MaVS in antiviral innate immunity (Kumar et al,
2006; Sun et al, 2006). nevertheless, how MaVS-mediated signalling
is engaged is not well understood. a recent study unveiled a crucial
role of ubiquitin chains in irF3 activation downstream from MaVS
through the ubiquitin-binding domains of nEMo (zeng et al, 2009).
in this model, nEMo is a sensor of lys 63 polyubiquitin chains that
activate tBK1 (Fig 2). However, the E3 ubiquitin ligase or ligases that
mediate irF3 activation by MaVS remain to be identified. a candi-
date is traF3, because it has been shown to be important for type i
iFn production by rlrs (oganesyan et al, 2006; Saha et al, 2006).
However, in some models, the knockdown of traF3 does not impair
the activation of the iFnβ promoter (zeng et al, 2009), suggesting that
other E3 ubiquitin ligases can compensate for the loss of traF3.
importantly, MaVS must be localized to mitochondria to exert
its function (Seth et al, 2005), suggesting that the mitochondrial
environ ment is required for signal transduction. in line with this,
two independent studies showed that MFn1—an effector of the
mitochondrial fusion machinery (chan, 2006)—positively regulates
MaVS-mediated innate antiviral responses (castanier et al, 2010;
onoguchi et al, 2010). in both cases, MaVS was shown to interact
with MFn1: after rlr activation, the complex MFn1–MaVS regu-
lates either MaVS redistribution along mitochondria (onoguchi et al,
STING
TBK1
NEMO
RLR activation
TRAF3/?
TRAF3/?
Ub
Ub
Ub
Ub
TANK
TBK1
NEMO
TANK
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
P
PP
P
IRF3
IRF3
MFN1
Low ROS
MFN2
MAVS
MAVS
ER
Mitochondrial
fusion
Low ∆Ψm
MFN2
MFN1
ER
MAVS
MAVS
STING
Fig 2 | Mitochondrial dynamics and innate immunity. In the mitochondrial outer membrane, MAVS interacts with both MFN1 and MFN2. MFN2 is a direct
MAVS inhibitor. RLR activation induces MAVS oligomerization, which recruits TRAF3 and other E3 ubiquitin ligases that catalyse Lys 63 polyubiquitination of
target proteins, including TRAF3. Polyubiquitin chains recruit TANK and NEMO, which in turn bind and activate TBK1, leading to the phosphorylation of IRF3.
Simultaneously, MFN1 leads to the redistribution of MAVS along mitochondria and a fusion of the mitochondrial network that promotes the interaction between
MAVS and STING. Low ΔΨm or decreased ROS inhibit MAVS-mediated signalling. ΔΨm, mitochondrial membrane potential; ER, endoplasmic reticulum; IRF,
interferon response factor; MAVS, mitochondria-associated viral sensor; MFN, mitofusin; NEMO, NF-κB essential modifier; RLR, RIG-I-like receptor; ROS,
reactive oxygen species; STING, stimulator of interferon genes; TANK, TRAF family member-associated NF-κB activator; TBK, TAK1-associated binding protein;
TRAF, TNF-receptor-associated factor.

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2010) or the elongation of the mitochondrial network (castanier
et al, 2010). although the role of MaVS redistribution remains to be
defined, it has been proposed that the elongation of the mitochon-
drial network linked to rlr activation enhances the association of
MaVS with Sting (castanier et al, 2010)—an antiviral signalling
adaptor localized in the endoplasmic reticulum membrane (ishikawa
& Barber, 2008)—therefore amplifying the antiviral response (Fig 1).
Surprisingly, although MFn1 seems to be a positive regulator in the
rlr pathway (castanier et al, 2010; onoguchi et al, 2010), its close
homologue MFn2 is a direct inhibitor of MaVS, a function that is
probably unrelated to its role in mitochondrial dynamics (yasukawa
et al, 2009). thus, although MFn1 and MFn2 have a similar func-
tion in mitochondrial fusion (chan, 2006), it seems that they have
opposite roles in viral innate immunity. as MFn1 and MFn2 both
engage in homotypic and heterotypic interactions on the mitochon-
drial outer membrane, associations with their respective partners
might ensure fine-tuning of MaVS-mediated signalling, in addition
to the regulation of mitochondrial fusion.
MaVS-mediated antiviral signalling is not only regulated by mito-
chondrial dynamics. two mitochondrial proteins, nlrX1 (Moore
et al, 2008) and gc1qr (Xu et al, 2009), have been recently iden-
tified as regulators of MaVS function that are involved in the inhi-
bition of the rigi- and MDa5-dependent antiviral response. the
autophagy-related protein atg5/12 (Jounai et al, 2007) and several
other cellular proteins such as pcBp2/aip4 (you et al, 2009), rnF5
(zhong et al, 2010) and plK1 (Vitour et al, 2009) have also been
implicated in the negative regulation of MaVS-mediated signalling.
interestingly, a recent study has reported that ΔΨm is crucial for this
pathway (Koshiba et al, 2011). cells in which the ΔΨm was dissi-
pated—treated with the protonophore cccp or lacking both MFn1
and MFn2—are defective in the antiviral innate immune response
after rlr, but not tlr3, activation. the precise role of ΔΨm in
Antiviral
innate response
▶ Mitochondrial fission
▶ Mitochondrial ∆Ψm
▶ Cell death
▶ Autophagy
▶ Autophagy
MAVS
Proline-rich
CARD
▶ Mitochondrial fission
▶ Mitochondrial ∆Ψm
▶ Cell death
NADPH
oxidase
TLR1/2/4
Phagosome
NLRX1
Cardiolipin
IRGM
TRAF6
ROS
ROS
ROS
MAMs
NLRP3
ASC
Pro-caspase 1
Caspase 1
CARD
CARD
PYD
PYD
NACHT
NAD
LRR
Active
caspase 1
IL-1β
IL-18
ECSIT
ECSIT
TRAF6
I
I
I
II
II
II
III
III
III
IV
IV
IV
NACHT
LRR
Fig 3 | Innate immune signalling at the mitochondria. On induction of mitochondrial reactive oxygen species (ROS), NLRP3 localizes to the mitochondrial-
associated endoplasmic reticulum membrane (MAM) with ASC and pro-caspase 1, inducing caspase-1 activation and the production of IL-1β and IL-18. MAVS is
located on the outer mitochondrial membrane and mediates antiviral signalling. On TLR1/2/4 stimulation, TRAF6 translocates to the mitochondria and interacts
with ECSIT, contributing to ROS production. NLRX1 is internalized into the mitochondrial matrix where it interacts with UQCRC2, a protein of the complex III
of the electron transfer chain, potentiating ROS production. IRGM binds to the mitochondrial lipid cardiolipin, influencing autophagy, mitochondrial fission,
mitochondrial ΔΨm and cell death. ASC, apoptosis-associated speck-like protein containing a CARD; ECSIT, evolutionarily conserved signalling intermediate in
Toll pathway; IL, interleukin; IRGM, immunity-related GTPase family M protein; LRR, leucine-rich repeat; MAVS, mitochondria-associated viral sensor; NAD,
nicotinamide adenine dinucleotide; NLRP, NOD-like receptor family, pyrin domain containing; NLRX, NOD-like receptor family member X; PYD, pyrin domain;
TLR, Toll-like receptor; TRAF, TNF-receptor-associated factor.

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MaVS-mediated signalling remains to be determined, although
Koshiba and colleagues suggest that loss of ΔΨm might prevent
the structural rearrangement of the MaVS complex, which could
exist as a readily available pool on the mitochondrial membrane to
provide a quicker response to viral infection (Koshiba et al, 2011).
Furthermore, loss of ΔΨm is associated with an intensive fragmen-
tation of the mitochondrial network that might prevent the associ-
ation of MaVS with the endoplasmic-reticulum-associated antiviral
signalling adaptor Sting (castanier et al, 2010; ishikawa & Barber,
2008). importantly, another conclusion of this study is that the inhi-
bition of atp synthesis—one of the most prominent functional role
of mitochondria—does not impair MaVS-mediated signalling.
an indirect role of mitochondria in the regulation of innate
immune responses is shown by the fact that roS modulate several
signalling pathways, including the nF-κB and JnK pathways, and
the caspase 1 inflammasome (naik & Dixit, 2011). the two main
sources of cellular roS are the mitochondria and the membrane-
associated naDpH oxidase (noX) and dual oxidase (DuoX)
complexes. noX2 and roS were recently shown to be required
for the triggering of efficient MaVS-mediated antiviral signalling
(Soucy-Faulkner et al, 2010). the authors also provide evidence that
noX2 is crucial for the expression of MaVS because noX2 down-
regulation diminishes MaVS mrna expression without affecting its
mitochondrial localization (Soucy-Faulkner et al, 2010).
although the function of mitochondria in MaVS-mediated anti-
viral signalling warrants further investigation because mitochondria
are essential for MaVS function (Seth et al, 2005), recent studies
have suggested that mitochondrial dynamics, ΔΨm and roS are
crucial regulators and/or effectors of this pathway (Fig 2).
Mitochondria: central platform for innate immunity
the identification of MaVS as a central adaptor protein of the rlr
pathway that localizes to the mitochondrial outer membrane pro-
vided the first example of a functional link between mitochondrial
function and innate immune signalling. notably, recent evidence
demonstrates that many host defence pathways are controlled by
this organelle (Fig 3).
NLRP3. nlrp3 is a crucial nlr protein implicated in the induction
of the caspase 1 inflammasome in response to a surprisingly wide
spectrum of microbial-associated and danger-associated molecular
signatures (see Benko et al (2008) for a recent comprehensive review
on this topic). the pleiotropic nature of the upstream activators of
nlrp3 has led to speculation that nlrp3 senses a common cellu-
lar signal triggered by paMps and DaMps rather than several indi-
vidual molecular entities. the nature of this common signal is still
open to debate, as evidence suggests that either lysosomal damage
or roS could act as nlrp3 activators (tschopp & Schroder, 2010).
although phagosome-associated roS generated by the naDpH
complex were first proposed to trigger nlrp3 responses, these
observations have been challenged by the fact that normal nlrp3
responses occur in cells carrying mutations that impair naDpH-
oxidase-dependent roS production (van Bruggen et al, 2010). the
group of Jürg tschopp recently proposed that mitochondria could
be the main source of roS contributing to nlrp3 activation (zhou
et al, 2011), providing a possible explanation for these conflicting
results. they found that rotenone and antimycin—two drugs that
block the mitochondrial respiratory chain and lead to the genera-
tion of mitochondrial roS—potently activate nlrp3. Similarly,
inhibition of autophagy results in the accumulation of defective
and roS-producing mitochondria, which potentiates nlrp3-
dependent inflammasome activation. interestingly, the authors
also demonstrated that mitochondria act as a molecular scaffold-
ing platform for the recruitment of several members of the nlrp3
inflammasome—including nlrp3 itself and the adaptor protein
aSc—in response to known nlrp3 activators, such as mono sodium
urate, aluminium hydroxide and nigericin (zhou et al, 2011). the
mechanism that underlies nlrp3 inflammasome recruitment to the
vicinity of roS-producing mitochondria remains unknown, and
future studies are necessary to identify the mitochondria-associated
docking complexes for nlrp3 inflammasome components.
TLRs. the engulfment of bacteria by phagocytic cells results in the
activation of numerous innate immune signalling pathways, includ-
ing those that promote microbicidal activity. roS generation is one
of the most ancient and efficient means to kill microorganisms and
it is functionally linked to phagocytosis through the upregulation of
the naDpH oxidase complex, which is localized at the surface of the
phagosome. tlr signalling enhances naDpH oxidase activity and,
in turn, roS generated by this complex potentiates tlr-mediated
induction of inflammatory pathways, such as those dependent on
nF-κB and Map kinases (gill et al, 2010). a recent study showed that
mitochondria might also have crucial roles in phagosome-associated
roS generation and in the connection to tlr signalling. indeed, acti-
vation of murine macrophages with ligands of cell-surface tlrs—
tlr1, tlr2 and tlr4—but not of endosomal tlrs—tlr3, tlr7,
tlr8 and tlr9—resulted in the production of mitochondria-derived
roS (West et al, 2011). interestingly, when cells phagocytosed latex
beads coated with tlr2 ligand pam3cSK4 or tlr4 ligand lpS, mito-
chondria accumulated near to phagosomes containing the latex
beads, an effect that was not observed if beads were coated with the
endosome-associated tlr9 ligand cpg Dna. the authors concluded
that engulfment of microbes, concomitant with tlr-mediated detec-
tion, resulted in mitochondrial accumulation around phagosomes
and local production of roS, which could contribute to the elimi-
nation of the engulfed microorganism. traF6—an E3 ligase crucial
for tlr signalling—is translocated to the mitochondria in response
to the engagement of tlr1/2/4 ligands, but not tlr3/9 ligands, and
mitochondrial EcSit protein was identified as a traF6-dependent
target of ubiquitination after macrophage activation by tlr1/2/4
ligands. importantly, triggering of the traF6–EcSit pathway at the
mitochondria was responsible for the recruitment of these organelles
to the vicinity of phagosomes and the induction of mitochondrial
roS. therefore, this study highlights the unexpected importance of
mitochondrial roS generation in phagosomal killing, and provides
a new example of how mitochondria can act as a signalling hub—in
this case, the traF6–EcSit pathway—for innate immune signalling
(West et al, 2011).
NLRX1. nlrX1 is a member of the nlr family that has a unique
n-terminal domain—which accounts for the letter ’X’ in its acro-
nym—that was found to contain a mitochondrial addressing
sequence (Moore et al, 2008; tattoli et al, 2008). Biochemical analy-
ses demonstrated that nlrX1 localizes to the mitochondrial matrix
(arnoult et al, 2009b). Strikingly, nlrX1 represents the first and
so far only example of a prr family member that targets this cel-
lular location, therefore implying that nlrX1 probably establishes
a fundamental link between mitochondrial functions and innate

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immunity. However, the fact that nlrX1 targets the mitochondrial
matrix is puzzling, as this confined location makes it unlikely that
the protein would directly detect microbial-derived molecular sig-
natures in an archetypal manner. thus, the exact function of nlrX1
is unclear. overexpression of nlrX1 was shown to induce roS pro-
duction (tattoli et al, 2008), which can be explained by its inter action
with uQcrc2, a matrix-facing component of the mitochondrial res-
piratory chain complex iii that has a crucial role in roS generation
(arnoult et al, 2009b). in Chlamydia-infected cells, nlrX1 potenti-
ates the roS production triggered by the pathogen, an effect that
is required for optimal bacterial growth (abdul-Sater et al, 2010).
interestingly, nlrX1 was also found to interact with MaVS, the cru-
cial adaptor protein of rlr pathways, on the cytosolic side of the
mitochondrial outer membrane, resulting in inhibition of MaVS-
dependent antiviral responses (Moore et al, 2008). However, how
nlrX1 interacts with MaVS remains unclear because these two pro-
teins are targeted to distinct mitochondrial subdomains that are sep-
arated by two membranes. as nlrX1 entry into mitochondria was
shown to depend on the inner membrane potential ΔΨm (arnoult
et al, 2009b), it is conceivable that dissipation of ΔΨm would result
in the retention of nlrX1 in the cytosol where the protein could
interact with and inhibit MaVS-dependent signalling. this hypo-
thesis has not been tested experimentally and it would be important
to determine whether viral infection could induce cytosolic reten-
tion of nlrX1. alternatively, nlrX1 could influence rlr signal-
ling through roS production, which has been shown to modulate
MaVS-dependent pathways (Soucy-Faulkner et al, 2010).
IRGM. irgM is a ubiquitously expressed human guanosine triphos-
phatase (Hunn et al, 2011) that functions in the innate immune con-
trol of intracellular pathogens. in contrast to the many murine irg
genes that are regulated by interferons, only two orthologues exist in
humans—IRGM and IRGC. IRGM was initially thought to be a
pseudo gene but has a role in the elimination of M. tuberculosis in
human macro phages (Singh et al, 2006). Specifically, IRGM was
demonstrated to be crucial in rapamycin-, starvation- and iFnγ-
induced autophagy to restrict the intracellular growth of M. tubercu-
losis in infected human macrophages (Singh et al, 2006). importantly,
single nucleotide polymorphisms in IRGM have been identified as
risk factors for crohn’s disease (parkes et al, 2007) and susceptibility
Cell trauma
Formyl
peptides
TLR9
FPR1
mtDNA
mtDNA
Systemic inflammatory
response
PMN
recruitment
Cytochrome c
release
Apoptosome
Deficient autophagyDeath signalling
Autophagy
IL-1β
Caspase 9
Caspase 9
Effector
caspase
Neutrophil
p38MAPK
Unknown
sensor
Pro-
caspase 9
APAF1
APAF1
Pro-
caspase 9
Fig 4 | Release of mitochondrial DAMPs triggers cell death and inflammatory pathways. (A) Severe trauma can induce the release of mitochondrial DNA
(mtDNA), which is detected by TLR9 located on the neutrophil surface, and thus activates p38 MAP kinase. N-formyl peptides are released by mitochondria and
recruit polymorphonuclear neutrophils (PMNs) by binding to the formyl-peptide receptor 1 (FPR1) expressed on their surface. (B) Autophagy-deficient cells
accumulate defective mitochondria, which release mtDNA into the cytosol, triggering activation of the inflammasome through an undefined cytosolic sensor.
(C) Cell death signals induce the release of cytochrome c into the cytosol, leading to the recruitment of APAF1 and pro-caspase 9 into a multiprotein complex
known as the apoptosome. After activation, caspase 9 induces apoptosis by cleaving effector caspases. DAMP, danger-associated molecular pattern; IL, interleukin;
MAPK, mitogen-activated protein kinase; TLR, Toll-like receptor.

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to tuberculosis (intemann et al, 2009) in different human popula-
tions. the mechanism of irgM-mediated autophagy was largely
unknown, but a recent study from the Deretic group has revealed
the importance of mitochondria in this process. irgM localizes to
mitochondria and regulates mitochondrial fission events, which had
been previously implicated in autophagic control of intracellular
pathogens (Singh et al, 2010). the localization of irgM to mito-
chondria is dependent on the interaction of irgM with cardiolipin,
a mitochondrial lipid found predominately in the inner mitochon-
dria membrane. additionally, a detailed analysis of irgM
spliced variants indicated that preferential overexpression of irgMd
isoform induces mitochondrial fission, mitochondrial depolariza-
tion and autophagy-independent cell death, leading to the release of
HMgB1, a major pro-inflammatory alarmin/DaMp (Singh et al,
2010). altogether, the dynamic regulation of mitochondria seems to
be a central aspect of the dual function of irgM in mediating
autophagy (cell survival) and apoptosis and/or necrosis (cell death)
in innate immunity. Future studies need to explore the role of
intra-mitochondrial irgM in the context of bacterial infection.
Modulation of innate immunity by mDAMPs
Mitochondria probably evolved from a bacterial ancestor that estab-
lished a symbiotic relationship with its host cell and, in this regard,
mitochondrial DaMps (herein termed ’mDaMps’) can be viewed as
intermediate entities between DaMps and paMps. not surprisingly,
mitochondria have several unique features in the cell and several
mitochondrial elements—such as cytochrome c, formyl peptides
and mitochondrial Dna (mtDna)—seem to have been selected
during evolution to act as mDaMps that alert the cell to damage in
the mitochondria. By far the most studied mDaMp is cytochrome c,
which triggers apoptotic cell death after its release from the mito-
chondrial inner membrane into the cytosol, where it interacts with
apaF1 to trigger the activation of the caspase-9-dependent pathways
of apoptosis. although mitochondria-dependent apoptotic cell death
is a crucial aspect of innate immune responses to pathogens, it has
been extensively reviewed elsewhere (garrido et al, 2006) and is not
discussed here. instead, we focus on more recent aspects of the link
between mDaMp liberation and innate immunity (Fig 4).
Circulating mDAMPs in trauma. zhang and colleagues hypothesized
that, in trauma patients and organ injuries without an open wound,
cellular damage would lead to the release of mitochondrial mol-
ecules that could operate as mDaMps and initiate an inflammatory
response (zhang et al, 2010a). the authors noticed a considerable
increase in the concentration of mtDna in the circulation of trauma
patients as compared with healthy volunteers. MtDna released
at the site of the injury recruited polymorphonuclear neutrophils
(pMns), which were also activated through a tlr9-dependent path-
way. in addition to mtDna, mitochondrial formyl peptides were
also proposed to act as mDaMps during injury. Stimulation of the
g-protein-coupled receptors Fpr1 and Fprl1—which mediate
the chemotactic and stimulatory effects of n-formyl-Met-leu-phe
(fMlp)—was shown to occur on pMns after exposure to mDaMps.
this indirectly suggests that endogenous mitochondrial formyl pep-
tides are liberated in vivo at the site of injury and in the circulation.
therefore, liberation of mDaMps can account for the induction of
sterile inflammation after organ injury and in trauma patients, which
can result in a systemic inflammatory response syndrome similar to
that observed during septic shock.
MtDNA and inflammasome activation. there has recently been
increasing interest in the identification of intracellular sensors of for-
eign Dna (Barber, 2011), and type i iFn induction and inflamma-
some activation seem to represent two of the main host responses
to intracellular Dna detection. Several prrs have been shown to
mediate the host response to intracellular Dna: zBp1/DlM1 is cru-
cial for the induction of type i iFn in some cell types, whereas in
others the conversion of Dna into rna by the rna polymerase iii
has been shown to redirect host responses to the rigi/MaVS path-
way (Barber, 2011). However, the physiological relevance of the lat-
ter system in the context of bacterial infection has been challenged
(Monroe et al, 2009). recently, the pyHin protein iFi16 (p204 in
mice) was also shown to detect cytosolic Dna, leading to the induc-
tion of type i iFn after recruitment and activation of Sting, which
seems to act as a key adaptor molecule for several intracellular Dna-
sensing systems (unterholzner et al, 2011). in addition, activation of
the caspase 1 inflammasome in response to foreign Dna requires
aiM2, another cytosolic pyHin protein (Barber, 2011).
MtDna can be released from damaged mitochondria (zhang
et al, 2010b) and—as mtDna has common features with bacterial
genomes—the potential role of mtDna in the activation of host
responses to cytosolic Dna is starting to be analysed. the inhibi-
tion of autophagy results in the accumulation of defective mito-
chondria and the cytosolic release of mtDna (nakahira et al, 2011).
interestingly, the presence of cytosolic mtDna—and not the accu-
mulation of damaged mitochondria—was shown to induce activa-
tion of the caspase 1 inflammasome in a partly aiM2-independent
manner. this suggests that an unknown cytosolic sensor of mtDna
might contribute to the activation of the inflammasome.
Concluding remarks
accumulating evidence has introduced the concept that mitochon-
dria—in addition to their well-known role in cell metabolic processes
and cell death—are crucial assembly platforms for innate immune sig-
nalling, as summarized in this review. among the outstanding ques-
tions that remain poorly understood (Sidebar a) is: why mitochondria?
an attractive possibility is that the convergence of multiple innate
immune pathways on this organelle would allow for a tight functional
integration of host defence and metabolic processes, although this
model has not yet been thoroughly tested. could it be that the activa-
tion of certain innate immune responses requires transition through an
’energetic checkpoint’? this could ensure that efficient cell- intrinsic
defence pathways would only be turned on in cells that remain fit.
another probable reason for the functional coupling of some innate
Sidebar A | In need of answers
(i)

(ii) What is the precise role of ΔΨm in MAVS-mediated signalling?
(iii) Do some BCL2 family members also regulate MAVS-mediated innate
immunity?
(iv) Which signals activate NLRX1 in the mitochondrial matrix?
(v) To what extent do mitochondrial metabolic functions have an impact
on the innate immune pathways that require this organelle as a
signalling hub?
(vi) What is the role of mitochondria in innate immunity in other
organisms, such as Drosophila?
Why does MAVS have to be anchored to the mitochondrial outer
membrane to exert its function?

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immune pathways to mitochondria is that this organelle is a major cel-
lular source of roS, which contribute in many ways to host defence
against pathogens. the topological organization of host defence path-
ways at the mitochondria might therefore have evolved because roS
are intrinsically unstable molecules that cannot diffuse into the cell.
Mitochondria have been studied for decades regarding their
role in cellular metabolism. Equally as unexpected as the discov-
ery 20 years ago that this organelle controls programmed cell death,
the mitochondrion now emerges as a key component in host innate
immune defence pathways. the implications of this new paradigm
are only starting to emerge.
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[From left to right] Ivan Tattoli, Stephen E. Girardin, Fraser Soares
& Damien Arnoult