Mitochondria in innate immune signaling
Introduction
Theories that mitochondria evolved from an independent prokaryotic organism to a symbiont residing within the cytosol of the eukaryotic cell suggest that this affiliation was to mutual benefit, with the mitochondrion generating energy for the cell and the cell providing reagents and security for the mitochondrion.1, 2 This theory of a bacterial origin for mitochondria fits nicely with findings that the unique components of mitochondria, when exposed, reveal their prokaryotic history and are recognized as foreign by innate immune receptors triggering an inflammatory response. Intriguingly, more recent studies suggest that the relevance of mitochondria to the innate immune response extends beyond their identification as invading bacteria and instead profoundly impact many separate aspects of innate immune responses.
Mitochondria are dynamic organelles with inner and outer membranes and an internal negatively charged matrix. Their most described function is to provide energy for the cell as the site of oxidative phosphorylation, generating 32 molecules of ATP per molecule of glucose. The vast majority of mitochondrial proteins are encoded by the nuclear DNA, transcribed and translated by the eukaryotic machinery, and then transported to their functional sites in the mitochondrion.3 Mitochondria do have their own circular DNA that encodes thirteen proteins necessary for oxidative phosphorylation along with the ribosomal and transfer RNAs needed for their translation.4 While a basic view of mitochondria may be to regard them as simply a source of ATP, the paths by which ATP is made as well as the other functions and activities of mitochondria are more complex with significant impacts upon the cell and the organism. Mitochondria are neither static nor discrete structures. In response to the conditions within the cell and both the state of and the demands being placed on the mitochondrion, mitochondria undergo fusion to combine with other mitochondria or fission to separate and form new mitochondria.5, 6 The balance of fusion and fission events has relevance beyond just determining the number of mitochondria to a cell as these processes also impact calcium regulation, generation of reactive oxygen species, and impact oxidative phosphorylation.7
Generation of ATP by mitochondria requires the negatively charged matrix that allows the passage of electrons over the electron transport chain, which consists of specialized complexes arranged on the inner mitochondrial membrane. Disruption of the negative charge of the matrix occurs in response to a number of stressors including antioxidants, oxidative phosphorylation substrates, and membrane uncoupling agents. This loss of negative potential results in a failure of ATP production and the generation and release of reactive oxygen species (ROS) that have the potential to cause widespread damage. Further, dysfunctional mitochondria can lose membrane integrity, allowing previously sequestered mitochondrial components to leak into the cytosol or out of damaged cells to the circulation.8, 9, 10 To limit the negative effects of ROS, damaged and dysfunctional mitochondria are removed through a process known as mitophagy.11
The innate immune response has a critical role in the detection and correction of both infectious and sterile insults. The response begins with the recognition of the insult, commonly through germline encoded receptors termed pattern recognition receptors (PRRs). These receptors bind to conserved features of microbes that identify them as foreign, or to endogenous molecules with specific modifications or in locations that reveal tissue or cellular injury.12, 13
This recognition of the insult, with the PRR bound by its specific activating ligand, triggers the immune response. While the precise characteristic of that immune response reflects both the type of innate immune cell being activated and the specific receptor and ligand, in general these innate responses are initiated quickly and also quickly escalate and alert additional cells and tissues of the disorder. These early signals of the initial innate immune response have effects throughout the organism, driving recruitment of additional innate immune cells to the site, alerting and activating the more specific adaptive immune response, and triggering the production of molecules needed for inflammation and repair by numerous tissues.14, 15, 16, 17, 18
Both structural and functional aspects of the mitochondria can impact the innate immune response. There are two broad categories by which this occurs: first, by directly activating the immune response and second, by modulating a response. Direct activation commonly reflects mitochondrial damage or pathology while modulation can occur as a byproduct of normal mitochondrial functions and processes. In this review, we will discuss the current literature that defines the interactions between mitochondria and the innate immune response.
Section snippets
Mitochondria Derived Alarmins of Innate Immunity
Pathogen associated molecular patterns, or PAMPs, are conserved features of invading organisms that serve to identify these organisms as foreign, while damage associated molecular patterns, or DAMPs, are endogenous molecules released or modified by sterile insults. Both DAMPs and PAMPs are specifically recognized as alarmins by discrete receptors of the innate immune system and trigger the appropriate immune response.12, 13 Their release by mitochondria is in response to cell stress and loss of
n-FP
In a manner similar to the initiation of protein translation in prokaryotes, mitochondrial initiation of protein translation requires N-formylated methionine (fMet), as mitochondrial translational initiation factor 2 can utilize only the formylated form of methionine, while unformylated methionine is used specifically for protein elongation.26 This unique characteristic of bacterial and mitochondrial proteins was proposed as a potential immune target well before the receptors and signaling
Cardiolipin
Cardiolipin is a unique phospholipid that was first identified in animal heart tissue and thus the family is known as cardiolipins. While the structure of cardiolipin varies, in general cardiolipin contains 2 phosphatidyl groups linked through a glycerol moiety. Cardiolipins are found in many prokaryotic membranes but in eukaryotic cells are limited to the mitochondrial membranes, primarily the inner mitochondrial membrane during normal mitochondrial function.32, 33 Cardiolipin contributes to
mtDNA
Mitochondrial DNA is a circular double strand of approximately 17Kbp that contains 13 mRNAs that encode the unique proteins of oxidative phosphorylation as well as related ribosomal RNAs and tRNAs. Similar to the mitochondrial use of bacterial-like machinery for protein translation discussed above, mitochondria DNA has characteristics consistent with prokaryotic nucleic acid. Mitochondrial DNA is a small molecule with methylation patterns discrete from nuclear DNA and is present at hundreds of
mROS
Mitochondrial reactive oxygen species (mROS) generation occurs via the electron transport chain (ETC) in response to altered substrate availability, hypoxia, or other abnormal mitochondrial or cellular conditions.52, 53 Electrons that leak from the matrix ETC chain at complex I-III react with oxygen to result in superoxide radicals. While it has long been held that these reactive molecules augment the immune response by attacking intracellular pathogens,54, 55 it is now established that their
Mitochondria and Innate Immune Responses
The many DAMPs of mitochondria can be released into the cytosol or extracellularly following infection, injury, or loss of cellular or mitochondrial homeostasis. These DAMPs can then be sensed by the numerous PRRs, which are germline encoded receptors that recognize the unique signatures of PAMPs and DAMPs and upon activation trigger the innate immune response.68 Based on their structures, locations, and functional specificities, PRRs are separated into discrete families that include the
Mitochondria and TLR Activation and Signaling
The TLRs are a family of transmembrane PRR, first identified in Drosophila, that are activated by ligand binding to their carboxy-terminal leucine rich repeat. Ten TLRs have been identified in humans, with TLRs 1, 2, 4, 5, 6, and 10 found on the cell surface and TRLs 3, 7, 8, and 9 spanning the endosomal membrane. Activation of TLRs results in signaling through the p38 and MAPK pathways with the resultant activation and nuclear localization of NFκB triggering the expression of proinflammatory
Mitochondria and the NLR family
Unlike the membrane-associated TLRs, the NLR family of pattern recognition receptors are localized in the cytoplasm of the cell where they are activated by PAMPs and/or DAMPs. Most members of the NLR family have a tripartite domain structure: carboxy-terminal leucine rich repeat, a central nucleotide binding domain, and a variable amino-terminal domain that is involved in protein-protein interactions. NLRs are divided into subfamilies by the class of amino-terminal domain: an acidic
NLRP3
NLRP3 was first described when its mutation was found to be causative to a group of autoinflammatory disorders, now collectively known as CAPS (cryopyrin-associated periodic syndromes).81, 82, 83 Subsequently, activation of the NLRP3 inflammasome has been linked to a wide array of infectious and sterile inflammatory disorders, including but not limited to bacterial, viral, and fungal infections, metabolic syndrome, ischemia-reperfusion injury, atherosclerosis, Alzheimer's disease, and gout.39
NLRX1
That the NLR family member NLRX1 interacts with mitochondria was initially suggested based on its novel amino-terminal domain. Rather than the pyrin or CARD domains found in other NLR family members, the NLRX1 protein begins with a putative mitochondrial targeting sequence. NLRX1 was confirmed experimentally to localize to the mitochondria but its exact mitochondrial location and its function have been less straight forward to determine.107, 108 Initially, NLRX1 was shown to be a negative
Mitochondria and RLRs
As viral genomes can undergo amplification in the cytoplasm of host cell, they are often inaccessible to detection by TLRs. Intact type I interferon responses to viral infections in cells lacking the sole TLR3 adaptor TRIF suggested a TLR-independent receptor pathway may exist that also generated these potent antiviral cytokines.120 The quest to identify these sensors of viral infections lead to the identification of the RNA helicase retinoic acid inducible protein I (RIG-I). RIG-I, along with
Mitochondria and cGAS-STING pathways
Although DNA was hypothesized to be immunogenic over a century ago, the sensors and immunologic pathways activated by cytosolic DNA remain only partially characterized.152 STING (stimulator of interferon genes) was identified 10 years ago as pivotal in the release of type I interferons.105, 153,154 This activation of STING was found to be in response to cytosolic DNA, and while more commonly considered to be of nuclear or microbial sources, this activation is also induced by mitochondrial DNA
Mitochondria and FPR signaling
Formyl peptide receptors (FPR) are a family of G protein coupled receptors expressed as transmembrane proteins on the surface of many hematopoietic as well as nonhematopoietic cells.172 They were first described on neutrophils and have been studied most extensively in regulating neutrophil migration and function.172, 173 These receptors are activated by n-FP, peptides produced by microbes or mitochondria that contain an amino-terminal formylated methionine (fMet).27, 28 There are 3 family
Mitochondrial metabolism and innate immunity
The focus of this section is the specific regulation of innate immune pathways by mitochondrial metabolism. For a broader discussion on, and insight into, immune regulation by metabolism the reader is referred to a recent in-depth review.186
Mitochondria use oxidative phosphorylation via the ETC and the tricarboxylic acid (TCA) cycle to generate ATP for cellular functions. The ETC consists of 5 multiprotein complexes on the inner mitochondrial membrane. Electrons are donated from NADH to complex
Concluding remarks
From their relatively humble beginnings as ancient bacteria, mitochondria have established themselves as regulators of sweeping aspects of mammalian function at both the cellular and organism level. This regulation extends well beyond simply providing critical bioenergetics and includes, but is not limited to, precise and nuanced control of innate immune activation and signaling. The advances in our understanding of the importance of mitochondria to the innate immune response along with
Acknowledgments
This work was supported by NIH grant AI104706 to Suzanne L. Cassel. We thank Fayyaz Sutterwala for discussing, reviewing, and editing the manuscript. The authors have read the journal's policy on disclosure of potential conflicts of interest and have no conflicts of interest to disclose. The authors have read the journal's authorship agreement and the manuscript has been reviewed by and approved by the authors.
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