Review Article Powering the Immune System: Mitochondria ...downloads.hindawi.com/journals/jir/2014/164309.pdfMitochondria represent a signi cant source of energy for eukaryotic cells

Review ArticlePowering the Immune System Mitochondria inImmune Function and Deficiency

Melissa A Walker1 Stefano Volpi2 Katherine B Sims1

Jolan E Walter3 and Elisabetta Traggiai4

1 Department of Neurology Massachusetts General Hospital Boston MA 02114 USA2Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health (DINOGMI)University of Genoa Genoa 16147 Genova Italy

3 Division of Allergy and Immunology Department of Pediatrics Massachusetts General Hospital for Children BostonMA 02114 USA4Novartis Institute for Research in Biomedicine Basel Switzerland

Correspondence should be addressed to Melissa A Walker walkermelissamghharvardeduand Elisabetta Traggiai elisabettatraggiainovartiscom

Received 16 June 2014 Revised 20 August 2014 Accepted 25 August 2014 Published 21 September 2014

Academic Editor Luca Gattinoni

Copyright copy 2014 Melissa A Walker et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Mitochondria are critical subcellular organelles that are required for several metabolic processes including oxidative phosphory-lation as well as signaling and tissue-specific processes Current understanding of the role of mitochondria in both the innate andadaptive immune systems is expanding Concurrently immunodeficiencies arising from perturbation of mitochondrial elementsare increasingly recognized Recent observations of immune dysfunction and increased incidence of infection in patients withprimarymitochondrial disorders further support an important role formitochondria in the proper function of the immune systemHere we review current findings

1 Introduction

Mitochondria represent a significant source of energy foreukaryotic cells These organelles are present in all celltypes and organ systems but are heterogenous in numbermorphology [1] and molecular composition [2] at the tissueand even subcellular levels [3] This raises the possibility oftissue- or system-specific roles for mitochondria and organ-specific pathobiology and clinical dysfunction

Current understanding of the breadth of the cellular rolesperformed by mitochondria is expanding Well-describedmitochondrial cellular functions include aerobic metabolismand redox reactions via the electron transport chain (ETC)reactive oxygen species (ROS) homeostasis mitochondrialuncoupling for heat production and regulation of apop-tosis and Ca++ homeostasis as well as certain enzymaticfunctions such as heme [4] and steroid synthesis [5] andregulation of cellular metabolism The diversity and scopeof the human ETC (ie the known redundancy of core

subunits in the ETC of mammals compared to bacteria andsignificant sequence homology noted between mammalianETC subunits and known enzymes of divergent function)suggest that the human respiratory chain may execute mul-tiple yet undescribed cellular or subcellular processes [6]which are cell or tissue specific These cellular processes andmitochondrial heterogeneity are the product of mitofusinand mitophagy regulated by mitochondrial proteins codedby the nuclear DNA (over 1100 genes are predicted) [7 8]and by the maternally inherited mitochondrial genome (22transfer ribonucleic aids (tRNAs) 2 ribosomal ribonucleicacids (rRNAs) and 13 proteins) [9]

It is not surprising thatmdashbeyond their classical rolein energy and metabolic mechanismsmdashrecent data haveproposed links between immune function and mitochon-drial processes Indeed as described in this review robustliterature now exists implicating mitochondria in the properfunction of the innate and adaptive immune system (asreviewed in [10ndash14]) Furthermore monogenetic disorders

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2014 Article ID 164309 8 pageshttpdxdoiorg1011552014164309

2 Journal of Immunology Research

of mitochondrial components may manifest with immunedysfunction Conversely immune deficiency andor immunedysfunction are increasingly noted in individuals with pri-mary mitochondrial disorders in which immunophenotypeshave not traditionally been described

2 Mitochondria and the InnateImmune System

A growing body of evidence links mitochondria to immunityin the basic scientific literature Mitochondria function assignaling platforms and participate in effector responses [10]most notably in the innate immune response to cellulardamage stress and infection by pathogensmdashparticularlyviralmdashvia linkages to effectors of pattern recognition receptor(PRR) signaling [11] PRRs recognize extracellular or intra-cellular highly conservedmotifs termed pathogen-associatedmolecular patterns (PAMPs) presented by infectious agentsThis recognition activates a signal cascade that ultimatelyresults in an inflammatory response involving cytokines andother downstream effectors Several PRRs are known tobe direct targets of pathogens resulting in the interferenceof the innate immune response to infection [15 16] PRRsinclude retinoic acid inducible gene- (RIG-I-) like receptors(RLRs) C-type lectin receptors (CLRs) Toll-like receptors(TLRs) and the nuclear oligomerization domain- (NOD-)like receptors (NLRs) Several downstream effectors of RLRsNLRs and TLRs link to the mitochondrion [12] RLRs havebeen most strongly linked to viral immunity via interactionswith the mitochondrial antiviral signaling protein (MAVS)that in turn activates NF-kappaB and IRF3 [17 18] NOD-like receptor family member X1 (NLRX1) a molecule thatcontains a mitochondrial addressing sequence [19 20] hasbeen shown to augment the MAVS antiviral response andlocalize to the mitochondrial matrix in biochemical assays[21 22]

PRRs also recognize motifs of endogenous moleculesreleased as a result of tissue injury in the absence ofinfection so-called damage-associated molecular patterns(DAMPs) including cytosolic ATP [23] uric acid [24] anddouble-stranded DNA [25] and a subset of proteins [2627] It is interesting to note that mitochondrial formyl pep-tides and mtDNA-encoded proteins are also potent DAMPs[28]

Additionally mitochondria influence antiviral signalingvia the production of reactive oxygen species (ROS) Over-expression of NLRX1 has been shown to induce reactiveoxygen species (ROS) potentially via an interaction witha component of ETC complex III [21] NOD-like receptorfamily pyrin domain containing 3 (NLRP3) translocatesfrom the endoplasmic reticulum to the mitochondrion whenactivated and mitochondrion-derived ROS are required foractivation of NLRP3 inflammasome [29] Likewise TNFreceptor associated factor 6 (TRAF6) a Toll-like receptor4 signaling pathway intermediate binds mitochondrion-localizing protein ECSIT (evolutionarily conserved signalingintermediate in Toll-like pathways) enhancing bactericidalactivity [30]

3 Mitochondria and Metabolic Regulation ofthe Adaptive Immune System

Extensive studies in T lymphocytes have shown thatmetabolism is tightly regulated during the entire lifespanof T cells [31] Upon encountering an antigen lymphocytesundergo a process of activation proliferation and differen-tiation toward specific effector states All these phenomenarequire changes in metabolism to enable cells to switchbetween a catabolic condition such as the quiescent stateof a memory cell to the anabolic condition such as thatrequired for activated cell division upon activation Thosemetabolic changes are required not only for lymphocyteplasticity but also to influence T cell fate modulation ofcellular metabolism has been proven to promote T celldifferentiation into specific lineages [32]

In the T cell glucose is the prevalent source of energyfor adenosine triphosphate (ATP) production As a firststep in the cytosol glucose is converted into pyruvateand then subsequently used in the mitochondria in thetricarboxylic acid (TCA) cycle leading to ATP productionthrough oxidative phosphorylation (OXPHOS) in the ETCAlternatively to glucose other sources of energy for T cellmetablismactivation are glutamine or fatty acids [14 31 33]

Resting naıve T cells are metabolically quiescent andmainly rely on OXPHOS for energy production [13] Uponcognate antigen encounter while oxidative phosphorylationremains an effective source of energy c-Myc upregulation[33] and estrogen related receptor alpa (EERalpha) signaling[34] activate the aerobic glycolytic pathway in order to meetthe increased energetic needs (reviewed in [35]) Similarlyto naıve T cells memory CD8 T cells are relatively quies-cent however when antigen is reencountered they respondin faster and stronger fashion This property has crucialconsequence in the metabolic status of memory T cellsIndeed several findings suggest that fatty acid oxidationand oxidative metabolism are crucial for memory gener-ation whereas glycolysis and glutaminolysis are requiredfor effector T cell function [36 37] Memory CD8 T cellsare characterized by the use of fatty acid oxidation as analternative source of energy upon activation [37] they havebeen shown to up-regulate carnitine palmitoyl transferase 1A(CPT1A) a mitochondrial membrane protein which controlsbeta-oxidation by regulating fatty acid transport across theouter mitochondrial membrane [37] Moreover mouse CD8memory T cells have more mitochondrial mass than CD8naıve T cells which promotes oxidative as well as glycolyticcapacity allowing CD8 T memory cells to respond morerapidly upon secondary exposure to the antigen [38] It hasalso been shown in human that CD8 effector memory T cells(CD8 EM) exhibit more glyceraldehyde-3-phosphate dehy-drogenase (GAPDH) activity at early time points Indeedafter CD28 engagement CD8 EM T cells rapidly produceIFN120574 and concomitantly switch to glycolysis being able tomount rapid secondary responses [39] Additional evidencesupports the role of glycolysis in the generation of terminallydifferentiated effector memory T cells while glycolysis inhi-bition preserves the formation of long-lived memory CD8T cells These results reveal a new potential mechanism for

Journal of Immunology Research 3

improving the efficacy of cell-based therapy in cancer aswell as chronic infectious diseases such as hepatitis B [40]Recently it has also been shown that in CD8 memory T cellsthe fatty acids (FA) needed for enhanced mitochondrial fattyacid oxidation (FAO) are not derived from external sourcesbut rather from the intrinsic expression of the lysosomalhydrolase LALwhich allows FAmobilization inCD8memoryrecall responses [41]

Similar to what was observed in the resting and activatedstate a different T cell metabolic signature has been observedin T effector populations CD4 helper Th1 Th2 and Th17specifically rely on glycolysis rather than mitochondrialmetabolism while T helper regulatory cells (Treg) show aparallel requirement for lipid metabolism glycolysis andOXPHOS [42ndash44] In particular the balance between Th17and Treg differentiation appears to be regulated by the cellspecific metabolic pathway through hypoxia inducible factor1120572 (HIF1120572) expression [35 36] Furthermore the metaboliccompetence of T lymphocytes is reprogrammed in chronicinflammatory disorders As an example naıve CD4 T cellsfrom rheumatoid arthritis patients are in a state of energydeprivation generating less ATP and being more susceptibleto apoptosis [45]

B lymphocyte metabolism has been poorly studied sofar but there is preliminary evidence that similar metabolicsignatures might reflect their activation and differentiationstates even if in a different fashion compared to T lympho-cytes In fact unlike in T cells naıve resting mouse B cellsshow activation of glycolysis Upon stimulation via eitherTLR4 or B cell receptor (BCR) B cells upregulate both aerobicglycolysis and mitochondrial oxygen consumption (a signalof increasedOXPHOS) through a c-Myc dependent pathway[46] Inhibition of the entire glycolytic pathway or selectivelyof mitochondrial oxidation inhibits antibody production invivo [47]

Recently Caro-Maldonado and colleagues have shownthat mouse B cells are metabolically distinct from T lympho-cytes in their response upon activation Instead of shiftingfrom oxidative phosphorylation to glycolysis they increasetheir metabolism maintaining a balance between the twopathways Additionally the same group demonstrated thatanergic B cells are metabolically quiescent while B cellschronically exposed to high BAFF level undergo a metabolicswitch rapidly increasing glycolysis on stimulation [48]As an additional example upon LPS stimulation mouse Blymphocytes acquire extracellular glucose to support de novolipogenesis necessary for proliferation and differentiationinto plasma cells [49] Finally it has been demonstratedthat autophagy a self-digestion strategy that sustains cellularmetabolism in a nutrient-depleted milieu is a fundamentalmechanism for plasma cell differentiation and function [50]Despite these initial reports of metabolic pathways thatinfluence mouse B cell differentiation including antibodyclass switch recombination affinity maturation memorygeneration and plasma cell formationmetabolic dependenceof human B cell pathways remains poorly understood

Release of ATP in the extracellular milieu represents animportant correlation between mitochondrial energy gen-eration and lymphocyte function (Figure 1) Several groups

have shown that after T cell activation via TCR increasedoxidative synthesis of ATP is followed by its release throughpannexin 1 channels [51ndash54] ATP in the extracellular space israpidly hydrolyzed to ADP AMP and adenosine by ectoen-zymes called ectonucleotidases [55] These purine moleculesrepresent the ligands for a class of membrane receptors calledpurinergic receptors that include ligand-gated ion channelsspecific for ATP (P2X receptors) G protein coupled receptorsspecific for ATP UTP and UDP-glucose (P2Y receptors)and G protein coupled receptor specific for adenosine (P1receptors) The effect of secreted extracellular ATP andpurinergic signaling contributes to the regulation of manycell types [56] acting mainly as a danger signal in the caseof NLRP3 activation IL1-120573 secretion by innate immune cellis regulated by ATP mediated P2X7 signaling and acts asa chemotactic molecule for neutrophil and macrophagesmigration [57] Autocrine purinergic stimulation by ATPthrough P2X receptors also plays a crucial role in amplifi-cation of T cell signal amplification for proper cell activationand effector differentiation acting through inhibition of Tregstability and favoring conversion towards TH17 cells [58]

In B lymphocytes we have shown a similar autocrine reg-ulation of cell effector function through purinergic signaling[59] In human and mouse B cells ATP is stored in Ca2+sensitive secretory vesicles which are released upon activa-tion through the BCR and TLR9 stimulation ExtracellularATP is then hydrolyzed by membrane bound ectoenzymes toadenosine The expression of one of those enzymes (ecto-51015840-nucleotidases 51015840NT or CD73) as well as consequent adeno-sine production correlates with naıve and IgMmemory B cellpropensity to undergo isotype class switch and differentiateinto IgG and IgA secreting plasma cells Remarkably a signifi-cant decrease in CD73 expression was observed in a cohort ofpatients with common variable immunodeficiency (CVID) adisease characterized by hypogammaglobulinemia increasedsusceptibility to infection and autoimmunity This resultconfirms previous observation of reduced 51015840-nucleotidaseactivity in patients with hypo- and agammaglobulinemia [6061]

4 Immune Phenotypes of Dysfunction inElements of Mitochondria

Primary mitochondrial disorders are a heterogeneous groupof multisystem disorders linked to dysfunction of the mito-chondrion an organelle critical to cellular metabolismThese disorders are diagnosed via a multifaceted approachinvolving clinical assessment family history genetic andbiochemical testing [62ndash64] Current clinical criteria forprimary mitochondrial disorders [53ndash55] include dysfunc-tion of the central nervous neuromuscular cardiovascularhematologic gastrointestinal endocrine renal ophthalmo-logic auditory hepatic and dermatologic systems Notablyimmune dysfunction is not currently included in clinicaldiagnostic criteria for primary mitochondrial disorders

Although immune dysfunction is not included in thecurrent diagnostic criteria for primary mitochondrial disor-ders a handful of monogenic disorders are known to resultin immune deficiency involving perturbation of components


ATP ATP

P2X7

Neutrophil MonocyteDC

ROSP2X7

IL-1

TLR-4

APC

(a)

P2X7TregT

ATP ADPAMP

Adenosine

T cell Regulatory T cell

ATP

CD73

CD39

(b)

BCR

IgG

IgA

B

B

CD 40

B

TLR-9

CD73

Adora2A

ATP

ADPAMP

AdenosineCD39

Native B cell Plasma cell

(c)

Figure 1 Immune cells regulation by extracellular purines Nucleotides such as ATP and ADP are released from apoptotic cells or activatedinflammatory cells through pannexin and connexin hemichannels or vesicular exocytosis In the extracellular milieu ATP has a direct effecton both innate and adaptive immune cells through the activation of P2X and P2Y receptors or after enzymatic conversion to adenosinethrough its binding to adenosine receptor (ADORA) Examples of those functions are represented by granulocyte activation and IL8 secretionfollowing P2Y receptors activation by ATP and IL1 secretion by monocyte and dendritic cells following concomitant P2X7 activation byATP and TLR4 binding of bacterial LPS (a) Extracellular ATP promotes T lymphocytes activation by binding P2X7 receptors a pathwaymodulated by regulatory T cell through ATP degradation to adenosine by the ectoenzymes expressed by those cells (b) In B lymphocyteadenosine production by the ectoenzymes expressed by subsets of B cells promotes class switch recombination and differentiation into IgGand IgA immunoglobulin secreting cells (c) (Modified from Schena et al [59])

(such as proteins and RNAs) coded by nuclear deoxyribonu-cleic acid (nDNA) and functioning in the mitochondrionThese disorders are not typically recognized as primarymito-chondrial disorders and affected individuals would not nec-essarily score as likely to be affected by Bernier criteria [62]Hereby we summarize dysfunction of three mitochondrialcomponents described in the context of primary immunode-ficiency not traditionally classified as primary mitochondrialdisorders adenylate kinase 2 (AK2) RNA component ofmitochondrial RNA processing endoribonuclease (RMRP)and TAZ genes (Table 1)

Adenylate kinase 2 (AK2) mutations have been associ-ated with sensorineural deafness and reticular dysgenesisa severe combined immune deficiency (SCID) with nearabsence of bone marrow lymphoid and myeloid elements[65] Recently a hypomorphic AK2 mutation with reducedenzyme expression was identified in a case of inflammatoryvariant of leaky SCID termed Omenn syndrome [66] Inthe latter report decreased T B and natural killer (NK)cell subsets were reported in conjunction with a very highfrequency of activatedmemoryT cells (CD45RA) and poorTcell proliferation tomitogen Curiously based on the reporteddata these patients would score as ldquounlikelyrdquo affectedwith a primary mitochondrial disorder by Bernier criteria[62]

The RNA component of mitochondrial RNA processingendoribonuclease (RMRP) contributes to ribosomal assem-bly telomere function and cell cycle control Pathogenicmutations in the RMRP gene result in Cartilage HairHypoplasia (CHH) syndrome characterized by dwarfismpredisposition to infections and variable degree of immunedeficiency with decreased emigrant T cells as well as poorproliferation and increased apoptosis of activated peripheralT cells [67]This presentation constitutes a ldquopossiblerdquo primarymitochondrial disorder as per Bernier criteria [62]

Barth syndrome secondary to mutation in the TAZgene [Xq28] results in mitochondrial dysfunction (via cardi-olipin deficiency) 3-methylglutaconic aciduria cardioskele-tal myopathy and persistent or intermittent neutropenia butwith normal killing activity [68] Based on reported datathese patients would score as ldquolikelyrdquo affected with a primarymitochondrial disorder by Bernier criteria [62]

5 Susceptibility to Infection in Patients withDocumented Mitochondrial Dysfunction

Conversely while there are currently no primary immun-odeficiencies also recognized as primary mitochondrial dis-orders there is likewise limited data regarding immune


Table 1 Primarymitochondrial disorders are recognized as a group ofmultisystem disorders with various features and supporting laboratoryfindings [62] Genetic ormetabolic diagnosesmdashwhen identifiablemdasharise fromperturbations of gene products localizing to themitochondrionthat may be nuclear or mitochondrially encoded [9] and are not necessary for a clinical diagnosis The immunodeficiencies above have nottypically been described as primary mitochondrial disorders but are linked to genetic defects of genes localizing to the mitochondrionWhilepublished cases of Barth syndrome and Cartilage Hair Hypoplasia would be scored as ldquopossiblerdquo or ldquolikely affectedrdquo based on criteria byBernier and colleagues published cases of Omenn syndrome score as ldquounlikely affectedrdquo by a primary mitochondrial disorder

Syndrome Gene Phenotypeimmunologicphenotype

Bernier criteriaclassification

Barth syndrome Tafazzin (TAZ)3-Methylglutaconicaciduria cardioskeletalmyopathiesneutropenia

Likely affected

Omenn syndrome Adenylate kinase (AK) 2

Inflammatory variant ofleaky severe combinedimmunodeficiency(L-SCID)

Unlikely affected

Cartilage HairHypoplasia

Mitochondrial RNAprocessing

endoribonuclease(RMRP)

Dwarfismpredisposition toinfections variableimmune deficiency with Tcell dysfunction

Possible

dysfunction predisposition to infection in patients with diag-nosed primary mitochondrial disorders To date remarkablerates of infection have been noted in cohorts specific totwo primary mitochondrial diseases mitochondrial neu-rogastrointestinal encephalomyopathy (MNGIE) [69] andcarnitine palmitoyltransferase 1A deficiency [70] as well asin a single case report of a patient with multiple electrontransport chain deficiencies [71] and a large cohort includingpatients with various primary mitochondrial disorders [72]

Currently available data on the rate of infections inpatients with primary mitochondrial disorders is retrospec-tive in design with variable control or baseline compar-isons In a retrospective clinical and genetic review of 92patientswithMNGIEmdashawell defined primarymitochondrialdisorder presenting with gastrointestinal dysmotility ptosisophthalmoplegia hearing loss and demyelinating peripheralneuropathymdash7 (76) were noted to have had recurrentinfections during their disease course (follow-up time is notspecified) [69] Mutations of the CPT1A gene can lead todeficiency of CPT1A (the metabolic enzyme that controlsmitochondrial fatty acid oxidation) an autosomal recessivemetabolic disorder of long chain fatty acid oxidation char-acterized by severe episodes of hypoketotic hypoglycemiausually occurring after fasting or illness [73] Recently astudy of the same hypomorphic CPT1A gene variant (Alaskavariant) in a homozygous state in a large cohort (152 or 25of 633 infants) of native Alaskan children demonstrated a sta-tistically significant (to 95 confidence interval) associationwith increased frequency of lower respiratory tract infection(55 versus 37 119875 = 0067) or acute otitis media (86 com-pared to 69 95 confidence interval 14ndash89) comparedto children who were heterozygous or noncarrier for thismutation Of note all medical care and clinical presentationsincluded in the analysis occurred prior to the diagnosis ofa CPT1A mutation and subgroup analysis was conducted toeliminate other potential confounders including availabilityof healthcare facilities [70] Interestingly Reichenbach andcolleagues have reported a case of an infant with electron

transport chain complex II III and IVmultiple enzyme defi-ciencies who presented with severe psychomotor retardationaxial hypotonia and abnormal nociception Immunologicalphenotyping revealed a decrease in all lymphocyte subsetsespecially CD8 T cells as well as hypogammaglobulinemiathat required immunoglobulin substitutive therapy T cellresponse to mitogens was normal The only genetic findingwas a heterozygous missense mutation of POLG of unclearsignificance [71]

We recently published a retrospective review [72] of theoccurrence of infection and systemic inflammatory immuneresponse syndrome that is SIRS [74] in a group of 97patients with a clinical diagnosis of a primary mitochondrialdisorder per published criteria [59] additionally supportedby biochemical andor genetic data Among the 97 patientsincluded in the analysis newborn to 68 years old pri-mary mitochondrial disorders with supporting biochemicalfindingsmdashprimarily defects in oxidative phosphorylationdemonstrated on muscle biopsymdashconstituted the majority(79 patients 81) and 34 (34) patients had various support-ing genetic findings (28 of whom carried a definitive molec-ular diagnosis) Patients experiencing recurrent urinary tractinfections and no other infections were excluded due to thehigh likelihood of comorbid neurogenic bladder in mito-chondrial disease Bacteremia in the setting of an in-dwellingcentral venous line was deemed significant only if it occurredat a rate exceeding that described for pediatric patients withcentral venous lines (irrespective of underlying diagnosis) ina prospective surveillance trial [75] pneumonia in the settingof respiratory insufficiency was only considered significant ifthe rate of pneumonia exceeded that reported in patients withnonmitochondrial neuromuscular disorders with similarventilatory support and gastrostomy tube status [76] Fortypatients (42) experienced serious or recurrent infections20 (21) with bacterial 7 (72) with bacterial and fungal 7(74) with bacterial and viral and 6 (62) with bacterialfungal and viral infections Common pathogens includedStaphlococcus aureus (15 patients affected) Candida albicans


(8) Clostridium difficile (6) Enterococcus (5) Escherichia coliPseudomonas aeruginosa (5) and respiratory syncytial virus(5) Twelve patients (13) experienced 1 episode of sepsisor a more severe SIRS categorization Three patients aged 3months 2 years and 3 years died of severe andor refractoryseptic shock Twenty-seven of the 40 patients with seriousor recurrent infection (68) received laboratory immunetesting Nine (9 of the total cohort 33 of patients withtesting) had laboratory documented immunodeficienciesincluding hypogammaglobulinemia (5 patients) transienthypogammaglobulinemia (1) and low IgA (1 patient) lowvaccine titers (3) low avidity of anti-pneumococcal antibod-ies (1) low memory B cells (2) and transiently low T cells[72]

6 Conclusion

In summary mitochondria perform essential roles inall eukaryotic organ systems including both universallyrequired and tissue-specific functions Current laboratorystudies and clinical observations are expanding our under-standing of mitochondrial function in both the innate andadaptive immune systems as well as documenting immunedysfunction in disorders affecting the mitochondrionFurther investigationmdashboth bench and clinicalmdashis requiredto further our understanding of the role of this criticalorganelle in immunity

As prolonged infection can cause regression inmilestonesin many mitochondrial patients an infection-free period notonly improves quality of life but also enables mitochondrialpatients to maximize their cognitive and physical develop-ment On the other hand patients with primary immunod-eficiency chronic infections or inflammatory disease maybenefit from detailed evaluation of mitochondrial functionand appropriate metabolic support to improve immunedysfunction

Conflict of Interests

Dr Jolan Walter is on the Virtual Advisory Board ofBaxter regarding IgHy a new formulation of subcutaneousimmunoglobulin The remaining authors have no conflict ofinterests regarding the publication of this paper

References

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[3] A M Cogswell R J Stevens and D A Hood ldquoPropertiesof skeletal muscle mitochondria isolated from subsarcolem-mal and intermyofibrillar regionsrdquo The American Journal ofPhysiologymdashCell Physiology vol 264 no 2 pp C383ndashC3891993

[4] J Chung C Chen and B H Paw ldquoHeme metabolism anderythropoiesisrdquo Current Opinion in Hematology vol 19 no 3pp 156ndash162 2012

[5] W L Miller ldquoSteroid hormone synthesis in mitochondriardquoMolecular and Cellular Endocrinology vol 379 pp 62ndash73 2013

[6] S B Vafai and V K Mootha ldquoMitochondrial disorders aswindows into an ancient organellerdquo Nature vol 491 no 7424pp 374ndash383 2012

[7] S Calvo M Jain X Xie et al ldquoSystematic identificationof human mitochondrial disease genes through integrativegenomicsrdquo Nature Genetics vol 38 no 5 pp 576ndash582 2006

[8] B KWagner T Kitami T J Gilbert et al ldquoLarge-scale chemicaldissection of mitochondrial functionrdquo Nature Biotechnologyvol 26 no 3 pp 343ndash351 101038nbt1387

[9] W J H Koopman P H G M Willems and J A M SmeitinkldquoMechanisms of disease monogenic mitochondrial disorders rdquoNew England Journal of Medicine vol 366 pp 1132ndash1141 2012

[10] A P West G S Shadel and S Ghosh ldquoMitochondria in innateimmune responsesrdquo Nature Reviews Immunology vol 11 no 6pp 389ndash402 2011

[11] L Galluzzi O Kepp and G Kroemer ldquoMitochondria masterregulators of danger signallingrdquo Nature Reviews Molecular CellBiology vol 13 no 12 pp 780ndash788 2012

[12] S M Cloonan and AM K Choi ldquoMitochondria commandersof innate immunity and diseaserdquo Current Opinion in Immunol-ogy vol 24 no 1 pp 32ndash40 2012

[13] R G Jones and C B Thompson ldquoRevving the engine signaltransduction fuels T cell activationrdquo Immunity vol 27 no 2 pp173ndash178 2007

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[15] E Meylan J Curran K Hofmann et al ldquoCardif is an adaptorprotein in the RIG-I antiviral pathway and is targeted byhepatitis C virusrdquoNature vol 437 no 7062 pp 1167ndash1172 2005

[16] R K Laguna E A Creasey Z Li N Valtz and R R Isberg ldquoALegionella pneumophila-translocated substrate that is requiredfor growth within macrophages and protection from host celldeathrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 103 no 49 pp 18745ndash18750 2006

[17] R B Seth L Sun C-K Ea and Z J Chen ldquoIdentification andcharacterization of MAVS a mitochondrial antiviral signalingprotein that activates NF-120581B and IRF3rdquo Cell vol 122 no 5 pp669ndash682 2005

[18] F Hou L Sun H Zheng B Skaug Q X Jiang and Z J ChenldquoMAVS forms functional prion-like aggregates to activate andpropagate antiviral innate immune responserdquo Cell vol 146 pp448ndash461 2011

[19] C B Moore D T Bergstralh J A Duncan et al ldquoNLRX1 is aregulator ofmitochondrial antiviral immunityrdquoNature vol 451no 7178 pp 573ndash577 2008

[20] I Tattoli L A Carneiro M Jehanno et al ldquoNLRX1 is amitochondrial NOD-like receptor that amplifies NF-120581B andJNK pathways by inducing reactive oxygen species productionrdquoEMBO Reports vol 9 no 3 pp 293ndash300 2008

[21] D Arnoult F Soaras I Tattoli C Castanier D J Philpottand S E Girardin ldquoAn N-terminal addressing sequence targetsNLRX1 to themitochondrialmatrixrdquo Journal of Cell Science vol122 no 17 pp 3161ndash3168 2009

[22] R Lin S Paz and J Hiscott ldquoTom70 imports antiviral immu-nity to the mitochondriardquo Cell Research vol 20 no 9 pp 971ndash973 2010


[23] J-M Boeynaems and D Communi ldquoModulation of inflam-mation by extracellular nucleotidesrdquo Journal of InvestigativeDermatology vol 126 no 5 pp 943ndash944 2006

[24] Y Shi J E Evans and K L Rock ldquoMolecular identification ofa danger signal that alerts the immune system to dying cellsrdquoNature vol 425 no 6957 pp 516ndash521 2003

[25] K Suzuki A Mori K J Ishii et al ldquoActivation of target-tissueimmune-recognition molecules by double-stranded polynu-cleotidesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 5 pp 2285ndash2290 1999

[26] P Scaffidi T Misteli and M E Bianchi ldquoRelease of chro-matin protein HMGB1 by necrotic cells triggers inflammationrdquoNature vol 418 article 6894 pp 191ndash195 2002

[27] D Foell H Wittkowski Z Ren et al ldquoPhagocyte-specificS100 proteins are released from affected mucosa and promoteimmune responses during inflammatory bowel diseaserdquo Journalof Pathology vol 216 no 2 pp 183ndash192 2008

[28] Q Zhang M Raoof Y Chen et al ldquoCirculating mitochondrialDAMPs cause inflammatory responses to injuryrdquo Nature vol464 no 7285 pp 104ndash107 2010

[29] R Zhou A Tardivel B Thorens I Choi and J TschoppldquoThioredoxin-interacting protein links oxidative stress toinflammasome activationrdquo Nature Immunology vol 11 no 2pp 136ndash140 2010

[30] A P West I E Brodsky C Rahner et al ldquoTLR signalling aug-ments macrophage bactericidal activity through mitochondrialROSrdquo Nature vol 472 no 7344 pp 476ndash480 2011

[31] J Lee M C Walsh K L Hoehn D E James E J Wherry andY Choi ldquoRegulator of fatty acid metabolism acetyl coenzyme acarboxylase 1 controls T cell immunityrdquo Journal of Immunologyvol 192 pp 3190ndash3199 2014

[32] G J W van der Windt and E L Pearce ldquoMetabolic switchingand fuel choice during T-cell differentiation and memorydevelopmentrdquo Immunological Reviews vol 249 no 1 pp 27ndash422012

[33] R Wang C P Dillon L Z Shi et al ldquoThe transcription factorMyc controls metabolic reprogramming upon T lymphocyteactivationrdquo Immunity vol 35 no 6 pp 871ndash882 2011

[34] R D Michalek V A Gerriets A G Nichols et al ldquoEstrogen-related receptor-120572 is a metabolic regulator of effector T-cellactivation and differentiationrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 108 no45 pp 18348ndash18353 2011

[35] N J Maciver R D Michalek and J C Rathmell ldquoMetabolicregulation of T lymphocytesrdquo Annual Review of Immunologyvol 31 pp 259ndash283 2013

[36] E L Pearce M C Walsh P J Cejas et al ldquoEnhancing CD8 T-cell memory by modulating fatty acid metabolismrdquoNature vol460 no 7251 pp 103ndash107 2009

[37] G JW van derWindt B Everts C-H Chang et al ldquoMitochon-drial respiratory capacity is a critical regulator of CD8+ T cellmemory developmentrdquo Immunity vol 36 no 1 pp 68ndash78 2012

[38] G J W van der Windt D OrsquoSullivan B Everts et al ldquoCD8memory T cells have a bioenergetic advantage that underliestheir rapid recall abilityrdquo Proceedings of the National Academyof Sciences of the United States of America vol 110 no 35 pp14336ndash14341 2013

[39] P M Gubser G R Bantug L Razik et al ldquoRapid effectorfunction of memory CD8+ T cells requires an immediate-earlyglycolytic switchrdquo Nature Immunology vol 14 pp 1064ndash10722013

[40] M Sukumar J Liu Y Ji et al ldquoInhibiting glycolytic metabolismenhances CD8+ T cell memory and antitumor functionrdquo TheJournal of Clinical Investigation vol 123 no 10 pp 4479ndash44882013

[41] D OrsquoSullivan G J van der Windt S C Huang et al ldquoMem-ory CD8(+) T cells use cell-intrinsic lipolysis to support themetabolic programming necessary for developmentrdquo Immu-nity vol 41 pp 75ndash88 2014

[42] E V Dang J Barbi H-Y Yang et al ldquoControl of TH17Tregbalance by hypoxia-inducible factor 1rdquo Cell vol 146 no 5 pp772ndash784 2011

[43] L Z Shi RWang GHuang et al ldquoHIF1120572-dependent glycolyticpathway orchestrates a metabolic checkpoint for the differen-tiation of T

11986717 and T

119903119890119892cellsrdquo The Journal of Experimental

Medicine vol 208 no 7 pp 1367ndash1376 2011[44] R D Michalek V A Gerriets S R Jacobs et al ldquoCutting

edge distinct glycolytic and lipid oxidative metabolic programsare essential for effector and regulatory CD4+ T cell subsetsrdquoJournal of Immunology vol 186 no 6 pp 3299ndash3303 2011

[45] Z Yang H Fujii S V Mohan J J Goronzy and C MWeyand ldquoPhosphofructokinase deficiency impairs ATP gener-ation autophagy and redox balance in rheumatoid arthritis Tcellsrdquo The Journal of Experimental Medicine vol 210 pp 2119ndash2134 2013

[46] F J Dufort B F Bleiman M R Gumina et al ldquoCuttingedge IL-4-mediated protection of primary B lymphocytesfrom apoptosis via Stat6-dependent regulation of glycolyticmetabolismrdquo Journal of Immunology vol 179 no 8 pp 4953ndash4957 2007

[47] C A Doughty B F Bleiman D J Wagner et al ldquoAntigenreceptor-mediated changes in glucose metabolism in B lym-phocytes role of phosphatidylinositol 3-kinase signaling in theglycolytic control of growthrdquo Blood vol 107 no 11 pp 4458ndash4465 2006

[48] A Caro-Maldonado R Wang A G Nichols et al ldquoMetabolicreprogramming is required for antibody production that issuppressed in anergic but exaggerated in chronically BAFF-exposedB cellsrdquo Journal of Immunology vol 192 pp 3626ndash36362014

[49] F J Dufort M Gumina N L Ta et al ldquoGlucose-dependent denovo Lipogenesis in B Lymphocytes a requirement for ATP-citrate lyase in LPS-induced differentiationrdquo The Journal ofBiological Chemistry 2014

[50] L Oliva and S Cenci ldquoAutophagy in plasma cell pathophysiol-ogyrdquo Frontiers in Immunology vol 5 article 103 2014

[51] U Schenk A M Westendorf E Radaelli et al ldquoPurinergiccontrol of T cell activation by ATP released through pannexin-1hemichannelsrdquo Science Signaling vol 1 no 39 article ra6 2008

[52] T Woehrle L Yip A Elkhal et al ldquoPannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptorsregulate T-cell activation at the immune synapserdquo Blood vol116 no 18 pp 3475ndash3484 2010

[53] L Yip T Woehrle R Corriden et al ldquoAutocrine regulation ofT-cell activation byATP release and P2X

7receptorsrdquoTheFASEB

Journal vol 23 no 6 pp 1685ndash1693 2009[54] A Filippini R E Taffs andM V Sitkovsky ldquoExtracellular ATP

in T-lymphocyte activation possible role in effector functionsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 87 no 21 pp 8267ndash8271 1990

[55] G G Yegutkin ldquoNucleotide- and nucleoside-convertingectoenzymes important modulators of purinergic signalling


cascaderdquo Biochimica et Biophysica Acta vol 1783 no 5 pp673ndash694 2008

[56] G Burnstock ldquoPurinergic signallingmdashan overviewrdquo NovartisFoundation symposium vol 276 pp 26ndash281 2006

[57] M Idzko D Ferrari andH K Eltzschig ldquoNucleotide signallingduring inflammationrdquo Nature vol 509 pp 310ndash317 2014

[58] U Schenk M Frascoli M Proietti et al ldquoATP inhibits thegeneration and function of regulatory T cells through theactivation of purinergic P2X receptorsrdquo Science Signaling vol4 no 162 p ra12 2011

[59] F Schena S Volpi C Faliti et al ldquoDependence of immunoglob-ulin class switch recombination in B cells on vesicular release ofATP and CD73 ectonucleotidase activityrdquo Cell Reports vol 3no 6 pp 1824ndash1831 2013

[60] S M Johnson M E North G L Asherson J Allsop R WWatts and A D Webster ldquoLymphocyte purine 5

1015840

nucleotidasedeficiency in primary hypogammaglobulinaemiardquo The Lancetvol 1 no 8004 pp 168ndash170 1977

[61] N L Edwards D B Magilavy J T Cassidy and I H FoxldquoLymphocyte ecto-51015840-nucleotidase deficiency in agammaglob-ulinemiardquo Science vol 201 no 4356 pp 628ndash630 1978

[62] F P Bernier A Boneh X Dennett C W Chow M A Clearyand D R Thorburn ldquoDiagnostic criteria for respiratory chaindisorders in adults and childrenrdquo Neurology vol 59 no 9 pp1406ndash1411 2002

[63] U A Walker S Collins and E Byrne ldquoRespiratory chainencephalomyopathies a diagnostic classificationrdquo EuropeanNeurology vol 36 no 5 pp 260ndash267 1996

[64] E Morava L van den Heuvel F Hol et al ldquoMitochondrialdisease criteria diagnostic applications in childrenrdquo Neurologyvol 67 no 10 pp 1823ndash1826 2006

[65] C Lagresle-Peyrou EM Six C Picard et al ldquoHuman adenylatekinase 2 deficiency causes a profound hematopoietic defectassociatedwith sensorineural deafnessrdquoNatureGenetics vol 41no 1 pp 106ndash111 2009

[66] L A Henderson F Frugoni G Hopkins et al ldquoFirst reportedcase of Omenn syndrome in a patient with reticular dysgenesisrdquoJournal of Allergy and Clinical Immunology vol 131 no 4 pp1227ndash1230 2013

[67] M A de La Fuente M Recher N L Rider et al ldquoReducedthymic output cell cycle abnormalities and increased apoptosisof T lymphocytes in patients with cartilage-hair hypoplasiardquoJournal of Allergy and Clinical Immunology vol 128 no 1 pp139ndash146 2011

[68] J L Jefferies ldquoBarth syndromerdquo The American Journal ofMedical Genetics C Seminars in Medical Genetics vol 163 no3 pp 198ndash205 2013

[69] C Garone S Tadesse and M Hirano ldquoClinical and geneticspectrum of mitochondrial neurogastrointestinal encephalom-yopathyrdquo Brain vol 134 no 11 pp 3326ndash3332 2011

[70] B D Gessner M B Gillingham T Wood and D M Koellerldquo Association of a genetic variant of carnitine palmitoyltrans-ferase 1A with infections in Alaska Native childrenrdquo Journal ofPediatrics vol 163 pp 1716ndash1721 2013

[71] J R Reichenbach R Schubert R Horvath et al ldquoFatal neo-natal-onset mitochondrial respiratory chain disease with T cellimmunodeficiencyrdquo Pediatric Research vol 60 no 3 pp 321ndash326 2006

[72] M A Walker N Slate A Alejos et al ldquoPredisposition to infec-tion and SIRS inmitochondrial disorders 8 yearsrsquo experience in

an academic centerrdquo Journal of Allergy andClinical Immunologyvol 2 no 4 pp 465ndash468 2014

[73] J-P Bonnefont FDjouadi C Prip-Buus SGobinAMunnichand J Bastin ldquoCarnitine palmitoyltransferases 1 and 2 bio-chemical molecular and medical aspectsrdquoMolecular Aspects ofMedicine vol 25 no 5-6 pp 495ndash520 2004

[74] M M Levy M P Fink J C Marshall et al ldquo2001 SCCMESICMACCPATS SIS international sepsis definitions confer-encerdquo Critical Care Medicine vol 31 no 4 pp 1250ndash1256 2003

[75] MWagner J Bonhoeffer T O Erb et al ldquoProspective study oncentral venous line associated bloodstream infectionsrdquoArchivesof Disease in Childhood vol 96 no 9 pp 827ndash831 2011

[76] J R Bach R Rajaraman F Ballanger et al ldquoNeuromuscularventilatory insufficiency effect of home mechanical ventilatoruse v oxygen therapy on pneumonia and hospitalization ratesrdquoThe American Journal of Physical Medicine and Rehabilitationvol 77 no 1 pp 8ndash19 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


of mitochondrial components may manifest with immunedysfunction Conversely immune deficiency andor immunedysfunction are increasingly noted in individuals with pri-mary mitochondrial disorders in which immunophenotypeshave not traditionally been described

2 Mitochondria and the InnateImmune System

A growing body of evidence links mitochondria to immunityin the basic scientific literature Mitochondria function assignaling platforms and participate in effector responses [10]most notably in the innate immune response to cellulardamage stress and infection by pathogensmdashparticularlyviralmdashvia linkages to effectors of pattern recognition receptor(PRR) signaling [11] PRRs recognize extracellular or intra-cellular highly conservedmotifs termed pathogen-associatedmolecular patterns (PAMPs) presented by infectious agentsThis recognition activates a signal cascade that ultimatelyresults in an inflammatory response involving cytokines andother downstream effectors Several PRRs are known tobe direct targets of pathogens resulting in the interferenceof the innate immune response to infection [15 16] PRRsinclude retinoic acid inducible gene- (RIG-I-) like receptors(RLRs) C-type lectin receptors (CLRs) Toll-like receptors(TLRs) and the nuclear oligomerization domain- (NOD-)like receptors (NLRs) Several downstream effectors of RLRsNLRs and TLRs link to the mitochondrion [12] RLRs havebeen most strongly linked to viral immunity via interactionswith the mitochondrial antiviral signaling protein (MAVS)that in turn activates NF-kappaB and IRF3 [17 18] NOD-like receptor family member X1 (NLRX1) a molecule thatcontains a mitochondrial addressing sequence [19 20] hasbeen shown to augment the MAVS antiviral response andlocalize to the mitochondrial matrix in biochemical assays[21 22]

PRRs also recognize motifs of endogenous moleculesreleased as a result of tissue injury in the absence ofinfection so-called damage-associated molecular patterns(DAMPs) including cytosolic ATP [23] uric acid [24] anddouble-stranded DNA [25] and a subset of proteins [2627] It is interesting to note that mitochondrial formyl pep-tides and mtDNA-encoded proteins are also potent DAMPs[28]

Additionally mitochondria influence antiviral signalingvia the production of reactive oxygen species (ROS) Over-expression of NLRX1 has been shown to induce reactiveoxygen species (ROS) potentially via an interaction witha component of ETC complex III [21] NOD-like receptorfamily pyrin domain containing 3 (NLRP3) translocatesfrom the endoplasmic reticulum to the mitochondrion whenactivated and mitochondrion-derived ROS are required foractivation of NLRP3 inflammasome [29] Likewise TNFreceptor associated factor 6 (TRAF6) a Toll-like receptor4 signaling pathway intermediate binds mitochondrion-localizing protein ECSIT (evolutionarily conserved signalingintermediate in Toll-like pathways) enhancing bactericidalactivity [30]

3 Mitochondria and Metabolic Regulation ofthe Adaptive Immune System

Extensive studies in T lymphocytes have shown thatmetabolism is tightly regulated during the entire lifespanof T cells [31] Upon encountering an antigen lymphocytesundergo a process of activation proliferation and differen-tiation toward specific effector states All these phenomenarequire changes in metabolism to enable cells to switchbetween a catabolic condition such as the quiescent stateof a memory cell to the anabolic condition such as thatrequired for activated cell division upon activation Thosemetabolic changes are required not only for lymphocyteplasticity but also to influence T cell fate modulation ofcellular metabolism has been proven to promote T celldifferentiation into specific lineages [32]

In the T cell glucose is the prevalent source of energyfor adenosine triphosphate (ATP) production As a firststep in the cytosol glucose is converted into pyruvateand then subsequently used in the mitochondria in thetricarboxylic acid (TCA) cycle leading to ATP productionthrough oxidative phosphorylation (OXPHOS) in the ETCAlternatively to glucose other sources of energy for T cellmetablismactivation are glutamine or fatty acids [14 31 33]

Resting naıve T cells are metabolically quiescent andmainly rely on OXPHOS for energy production [13] Uponcognate antigen encounter while oxidative phosphorylationremains an effective source of energy c-Myc upregulation[33] and estrogen related receptor alpa (EERalpha) signaling[34] activate the aerobic glycolytic pathway in order to meetthe increased energetic needs (reviewed in [35]) Similarlyto naıve T cells memory CD8 T cells are relatively quies-cent however when antigen is reencountered they respondin faster and stronger fashion This property has crucialconsequence in the metabolic status of memory T cellsIndeed several findings suggest that fatty acid oxidationand oxidative metabolism are crucial for memory gener-ation whereas glycolysis and glutaminolysis are requiredfor effector T cell function [36 37] Memory CD8 T cellsare characterized by the use of fatty acid oxidation as analternative source of energy upon activation [37] they havebeen shown to up-regulate carnitine palmitoyl transferase 1A(CPT1A) a mitochondrial membrane protein which controlsbeta-oxidation by regulating fatty acid transport across theouter mitochondrial membrane [37] Moreover mouse CD8memory T cells have more mitochondrial mass than CD8naıve T cells which promotes oxidative as well as glycolyticcapacity allowing CD8 T memory cells to respond morerapidly upon secondary exposure to the antigen [38] It hasalso been shown in human that CD8 effector memory T cells(CD8 EM) exhibit more glyceraldehyde-3-phosphate dehy-drogenase (GAPDH) activity at early time points Indeedafter CD28 engagement CD8 EM T cells rapidly produceIFN120574 and concomitantly switch to glycolysis being able tomount rapid secondary responses [39] Additional evidencesupports the role of glycolysis in the generation of terminallydifferentiated effector memory T cells while glycolysis inhi-bition preserves the formation of long-lived memory CD8T cells These results reveal a new potential mechanism for













ATP ATP

P2X7


ROSP2X7

IL-1

TLR-4

APC

(a)

P2X7TregT

ATP ADPAMP

Adenosine


ATP

CD73

CD39

(b)

BCR

IgG

IgA

B

B

CD 40

B

TLR-9

CD73

Adora2A

ATP

ADPAMP

AdenosineCD39


(c)













Likely affected



Unlikely affected





Possible







6 Conclusion





References













































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























ATP ATP

P2X7


ROSP2X7

IL-1

TLR-4

APC

(a)

P2X7TregT

ATP ADPAMP

Adenosine


ATP

CD73

CD39

(b)

BCR

IgG

IgA

B

B

CD 40

B

TLR-9

CD73

Adora2A

ATP

ADPAMP

AdenosineCD39


(c)













Likely affected



Unlikely affected





Possible







6 Conclusion





References













































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ATP ATP

P2X7


ROSP2X7

IL-1

TLR-4

APC

(a)

P2X7TregT

ATP ADPAMP

Adenosine


ATP

CD73

CD39

(b)

BCR

IgG

IgA

B

B

CD 40

B

TLR-9

CD73

Adora2A

ATP

ADPAMP

AdenosineCD39


(c)













Likely affected



Unlikely affected





Possible







6 Conclusion





References













































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Likely affected



Unlikely affected





Possible







6 Conclusion





References













































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















6 Conclusion





References













































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































11986717 and T
























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























1015840
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Powering the Immune System: Mitochondria ...downloads.hindawi.com/journals/jir/2014/164309.pdfMitochondria represent a signi cant source of energy for eukaryotic cells