Mitochondria at the interface between neurodegeneration and neuroinflammation

Mitochondria at the interface between neurodegeneration and neuroinflammation

Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology jou...

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Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb

Mitochondria at the interface between neurodegeneration and neuroinflammation Verian Bader, Konstanze F. Winklhofer



Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Germany

A R T I C LE I N FO

A B S T R A C T

Keywords: cGAS/STING Inflammasome Innate immunity Mitochondria Neurodegeneration Neuroinflammation

Mitochondria are essential organelles for the maintenance of neuronal integrity, based on their manifold functions in regulating cellular metabolism and coordinating cell death and viability pathways. Accordingly, mitochondrial damage, dysfunction, or ineffective mitochondrial quality control is associated with neurological disorders and can occur as a cause or consequence of neurodegenerative diseases. Recent research revealed that mitochondria play a central role in orchestrating both innate and adaptive immune responses, thereby providing a link between neurodegenerative and neuroinflammatory processes. Here we summarize new insights into the complex interplay between mitochondria, innate immunity and neurodegeneration.

1. Introduction Mitochondria are cellular organelles of proteobacterial origin and as such need to be protected from antimicrobial immune responses. On the other hand, mitochondria have been co-opted by eukaryotic cells not only to promote efficient host immune responses but also to react to cellular damage (rev. in [1,2]). As a first line of defense, innate immune signaling pathways are activated by invading pathogens to accomplish host cell protection. Intracellular bacteria that escape the endocytic pathway expose pathogen-associated molecular patterns (PAMPs), such as bacterial cell wall components or pathogen-derived nucleic acids, which are sensed by pattern recognition receptors (PRRs). PRR-

mediated activation of innate immune signaling pathways induces primarily transcriptional reprogramming of the host cell. For example, activation of the NF-κB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) and MAPK (mitogen-activated protein kinase) signaling cascades results in increased gene expression of pro-inflammatory cytokines. Activation of the IRF3 (interferon regulatory factor 3) pathway promotes a type I interferon (IFN) response via IFN-β and IFN-α expression. Whereas host cells aim at restricting bacterial proliferation and eliminating intracellular pathogens by specific autophagy, called xenophagy, intracellular bacteria have evolved different strategies to establish an optimal intracellular niche for their replication and to avoid clearance by xenophagy (rev. in [3,4]).

Abbreviations: AD, Alzheimer's disease; APP, amyloid precursor protein; Alu, arthrobacter luteus; ASC, apoptosis-associated speck-like protein containing a CARD; ATP, adenosine triphosphate; BAK, BCL-2 antagonist/killer 1; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2; BMDM, bone-marrow-derived macrophages; cAMP, cyclic adenosine monophosphate; CD, cluster of differentiation; cGAMP, 2′3′-cyclic cGMP-AMP; cGAS, cyclic GMP-AMP synthase; CYLD, lysine 63 deubiquitinase associated with Cylindromatosis; DAMP, danger-associated molecular pattern; dsRNA, double-stranded ribonucleic acid; EAE, experimental autoimmune encephalomyelitis; ERGIC, ER-Golgi intermediate compartment; FPR, formyl peptide receptor; HIV, human immunodeficiency virus type-1; IFN, interferon; IκB, inhibitor of kappa B; IKK, IκB kinase; IL, interleukin; IRF3, interferon regulatory factor 3; LC3, microtubule-associated proteins 1A/1B light chain 3; LPS, lipopolysaccharide; LUBAC, linear ubiquitin chain assembly complex; MAPK, mitogen-activated protein kinase; MAPT, microtubule-associated protein tau; MDV, mitochondria-derived vesicles; mtDNA, mitochondrial DNA; MAVS, mitochondrial antiviral signaling protein; mtROS, mitochondrial reactive oxygen species; MPT, mitochondrial permeability transition; MARCH7, membrane associated ring−CH-type finger 7; MDA5, melanoma differentiation associated gene 5; NADH, nicotinamide adenine dinucleotide; NF-κB, nuclear factor 'kappa-light-chain-enhancer' of activated B-cells; NEMO, NF-kappa-B essential modulator; NLRP3, nucleotidebinding domain and leucine-rich repeat containing protein 3; P2 × 7, P2X purinoceptor 7; PAMP, pathogen-associated molecular pattern; PD, Parkinson's disease; PINK1, PTEN-induced kinase 1; PSEN, presenilin-1; PRR, pattern recognition receptor; PolG, DNA polymerase gamma; RIG-I, retinoic acid inducible gene-I; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RLR, retinoic acid inducible gene-I-like receptor; ROS, reactive oxygen species; SAVI, STING-associated vasculopathy with onset in infancy; SHARPIN, SHANK-associated RH domain interactor; ssRNA, single-stranded ribonucleic acid; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TFAM, mitochondrial transcription factor A; TLR, Toll-like receptor; UBL, ubiquitin-like ⁎ Correspondinf author at: Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany. E-mail address: [email protected] (K.F. Winklhofer). https://doi.org/10.1016/j.semcdb.2019.05.028 Received 29 March 2019; Received in revised form 28 May 2019; Accepted 29 May 2019 1084-9521/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Verian Bader and Konstanze F. Winklhofer, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.05.028

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Fig. 1. Mitochondria and innate immune responses. DAMPs originating from mitochondria, such as mtDNA, cardiolipin, ATP, and formyl peptides can trigger various innate immune signaling pathways in a cell-intrinsic or -extrinsic manner. Dependent on the activating stimulus and the cellular context, downstream effector protein complexes can induce expression of type I interferons or proinflammatory cytokines. FPR, formyl peptide receptor; P2X7, purinergic receptor for ATP.

2. Mitochondria and inflammasomes

The outer mitochondrial membrane usually protects mitochondria from innate immune responses. However, several stress conditions can damage the outer and inner mitochondrial membrane and induce the release of mitochondrial components, such as mitochondrial (mt) DNA or cardiolipin. These mitochondrial components are recognized by PRRs as danger-associated molecular patterns (DAMPs), indicating cellular damage and thus eliciting innate immune responses. PRRs that play a role in the detection of both bacterial PAMPs and mitochondrial DAMPs are inflammasomes, cyclic GMP-AMP synthase (cGAS), and Toll-like receptors (TLRs) at the plasma membrane or endosomes (Fig. 1). Notably, expression of most PRRs is not restricted to specialized innate immune cells, such as macrophages, microglia, dendritic cells or neutrophils, but also occurs in a large number of non-immune cells, including neurons.

2.1. The NLRP3 inflammasome Various PAMPs and DAMPs can induce the assembly and activation of inflammasomes, cytosolic multimeric protein complexes that modulate host immune responses via autoproteolytic cleavage and activation of caspase-1 (rev. in [5–9]). Several cytosolic PRRs can form inflammasomes depending on the mode of stimulation. The most widely studied inflammasome is the NLRP3 (nucleotide-binding domain and leucine-rich repeat containing protein 3, also known as NALP3) inflammasome, comprising the sensor protein NLRP3, the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and pro-caspase-1. Activation of NLRP3 inflammasomes is a two-step 2

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release of mtDNA in response to lipopolysaccharide (LPS) and ATP treatment, which was dependent on NLRP3 inflammasomes and mitochondrial ROS and resulted in caspase-1 activation [11]. In the model used by Nakahira et al., mtDNA release was proposed to be mediated by mitochondrial permeability transition (MPT), based on an inhibitory effect of cyclosporine A in bone-marrow-derived macrophages (BMDMs), which is an inhibitor of the MPT pore component cyclophilin D. However, a study from James Vince's laboratory showed that deletion of cyclophilin D did not impair inflammasome activation, suggesting that cyclosporine A has off-target effects that may influence NLRP3 activation [21]. The view that ROS and mtDNA released from damaged mitochondria are a major culprit for inflammasome activation was challenged by the latter study, demonstrating that loss of the E3 ubiquitin ligase Parkin in macrophages has no effect on NLRP3 inflammasome function [21]. Parkin is an E3 ubiquitin ligase that is recruited to depolarized mitochondria through stabilization of the mitochondrial kinase PINK1, which activates Parkin via phosphorylation of ubiquitin and the UBL (ubiquitin-like) domain of Parkin (rev. in [22–24]). As a consequence, several autophagy adaptor proteins are recruited and depolarized mitochondria are then eliminated by mitophagy. Mutations in the genes encoding Parkin and PINK1 are linked to autosomal recessive Parkinsonism, suggesting that accumulation of damaged mitochondria is a pathogenic mechanism in Parkinson's disease (PD). Allam et al. observed that BMDMs from Parkin-deficient mice do not show differences in IL-1β production or caspase-1 activation upon activating NLRP3 inflammasomes by canonical stimuli. In contrast, Michael Karin and coworkers found that Parkin-mediated mitophagy via the recruitment of p62 to damaged mitochondria counteracts NLRP3 inflammasome activation in macrophages [25]. NFκB acts as a primer for NLRP3 inflammasome activation by inducing gene expression of pro-IL-1β, pro-IL-18 and NLRP3. Zhong et al. reported that by transcriptionally upregulating p62 expression and thereby facilitating Parkin-mediated mitophagy, NF-κB promotes also the removal of damaged mitochondria and thereby limits its pro-inflammatory activity in macrophages, suggesting a negative regulatory loop. Another study revealed an increase in stimulus-induced NLRP3 inflammasome activation in microglia and BMDMs from both Parkinand PINK1-deficient mice [26]. In Parkin-deficient cells, this effect was accompanied by reduced expression of A20, which has been described as a negative regulator of NLRP3 inflammasome activation [27–29]. A20 is a deubiquitinase and scaffold protein that has been implicated in NF-κB pathway regulation. Based on its activity to remove polyubiquitin chains of different linkages, A20 has been proposed to act as a negative regulator of NF-κB signaling. However, mice expressing catalytically inactive A20 do not show an inflammatory phenotype in contrast to A20-deficient mice, suggesting that the scaffold function of A20 is more relevant [30,31]. A20 binds to linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC) and protects these chains from cleavage by the deubiquitinase CYLD, an effect that may also be relevant in modulating inflammasome activity and cell death regulation [32–34]. In this context, it is noteworthy that Parkin can increase LUBAC-mediated linear ubiquitination, most likely by acting as a priming E3 ubiquitin ligase for LUBAC. LUBAC assembles linear ubiquitin chains preferentially on pre-existing K63-linked ubiquitin chains [35–37] and Parkin adds K63-linked ubiquitin chains to the LUBAC substrates NEMO and RIPK1 [38–41]. Ubiquitination is a highly versatile posttranslational modification based on the fact that polyubiquitin chains can be formed by eight different interubiquitin linkages using one of seven lysine residues or the N-terminal ubiquitin. The latter is called M1-linked or linear ubiquitination and acts as a signaling platform by recruiting interacting proteins. LUBAC is the only E3 ligase complex capable of generating linear ubiquitin chains and is composed of three subunits, the catalytically active E3 ubiquitin ligase HOIP, and the HOIP-activating proteins HOIL-1 and SHARPIN. Notably, LUBAC is a core component of pathways activating NF-κB and has been implicated in innate and

process, starting with priming by transcriptional upregulation of inflammasome components via NF-κB and post-translational modifications, such as deubiquitination of NLRP3. The second step can be induced for example by alterations in ion homeostasis (potassium efflux, calcium influx), pore-forming toxins, extracellular ATP, and lysosomal rupture upon uptake of particulate matter (uric acid crystals, crystalline cholesterol, fibrillar amyloid-beta or α-synuclein). Active caspase-1 cleaves pro-interleukin (IL)-1β and pro-IL-18 into the mature inflammatory forms that are secreted. In addition, active caspase-1 can mediate pyroptosis, a pyrogenic inflammatory form of cell death, induced by processing of the pore-forming protein gasdermin D. It has been reported that mitochondrial ROS, mtDNA, particularly oxidized mtDNA, and cardiolipin externalization mediate activation of NLRP3 inflammasomes, although the exact role of mitochondria in this process is still controversial [10–13]. 2.2. Mitochondria, NLRP3 inflammasomes and pathogens Mitochondria have been implicated in inflammasome activation upon viral and bacterial infections. The mitochondrial antiviral signaling protein MAVS was reported to contribute to NLRP3 inflammasome activation induced by RNA viruses. Sensing of viral RNA by RLRs (retinoic acid inducible gene-I-like receptors), including RIG-I and MDA5 (melanoma differentiation associated gene 5), induces their binding to mitochondrial MAVS, polymerization of MAVS and recruitment of adaptor proteins and kinases, resulting in the activation of IRF3 and NF-κB transcription factors [14]. MAVS activated by viral dsRNA recruits the NLRP3 inflammasome to mitochondria and enhances its activation, most likely by increasing the propensity to encounter mitochondrial ROS [15,16]. Another study reported that sensing of cytosolic dsRNA triggers MAVS-dependent membrane permeabilization, which in turn leads to potassium efflux and NLRP3 inflammasome activation [17]. Moreover, the glycolytic enzyme hexokinase, localized at the outer mitochondrial membrane, has been identified as a PRR for N-acetylglucosamine, a degradation product of bacterial peptidoglycan. Upon binding of N-acetylglucosamine, hexokinase is inhibited and dissociates from the outer mitochondrial membrane, which is sufficient to activate NLRP3 inflammasomes, possibly via release of mtDNA [18]. Thus, Nacetylglucosamine-induced inhibition of hexokinase triggers an inflammatory response by inhibition of the glycolytic pathway, suggesting that metabolic perturbations can be sensed as danger signals. In support of this notion, Sanman et al. reported that disruption of the glycolytic flux for example by Salmonella Typhimurium causes NLRP3 inflammasome activation via decreased NADH and increased mitochondria-derived ROS [19]. Interestingly, restoring metabolism downstream of glycolytic inhibition was sufficient to prevent inflammasome activation. In conclusion, NLRP3 inflammasome activation is induced by a remarkably wide range of infectious and cellular stress conditions. The integrative mechanism leading to a unified response is not fully understood, but it seems plausible that diverse stimuli converge to mitochondrial damage with subsequent release of mtROS, mtDNA or exposure of cardiolipin. 2.3. Regulation of NLRP3 inflammasome activity In this context it is interesting to note that in 2011 two studies identified mitophagy as a protective mechanism to limit the release of mitochondrial ROS and mtDNA from damaged mitochondria [11,20]. Zhou et al. reported that pharmacological or genetic inhibition of autophagy/mitophagy by silencing Beclin 1 or ATG5 in THP1 macrophages induces increased mitochondrial ROS generation through accumulation of damaged mitochondria that is sufficient to activate NLRP3 inflammasomes [20]. In the study performed by Nakahira et al., depletion of LC3B or Beclin 1 in peritoneal macrophages promoted the 3

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that mitochondrial dysfunction can contribute to neuroinflammation in PD. Oral administration of the small-molecule NLRP3 inhibitor MCC950 in rodent PD models inhibited inflammasome activation and mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates, indicating that microglial NLRP3 may be a sustained source of neuroinflammation [58]. Beneficial effects of NLPR3 inflammasome inhibition were also observed in a mouse model of cerebellar ataxia resulting from a point mutation in the gene encoding Elongator complex subunit 6 [60]. This mutation caused destabilization of the Elongator protein complex, which functions as a global translation regulator, and induced protein misfolding, proteotoxic stress and Purkinje neuron degeneration paralleled by substantial microgliosis. Inhibition of the NLPR3 inflammasome by MCC950 attenuated Purkinje neuron degeneration and the onset of ataxia in mutant mice. There is increasing evidence that inflammasomes contribute to inflammatory responses in Alzheimer's disease (AD). NLRP3 inflammasome activation upon phagocytosis of extracellular amyloid-beta peptide by microglia and subsequent lysosomal damage and cathepsin B release was first reported by Halle et al. [61]. Activation of microglial NLRP3 inflammasomes by amyloid-beta peptide has now been observed in various cellular and mouse models of AD and confirmed in human AD brain [53]. Supporting its pathophysiological relevance, inhibition of the NLRP3 inflammasome by NLRP3 depletion protects transgenic APP/PS1 mice carrying mutations associated with familial AD (APP KM670/671 N L (Swedish), PSEN1 deltaE9) from neuroinflammation and cognitive impairment [62]. In addition, ASC specks, supramolecular assemblies of ASC fibrils that form upon inflammasome activation, are released from microglia undergoing pyroptosis and bind to extracellular amyloid-beta peptides. This interaction increases amyloidbeta peptide aggregation and spreading of pathology [63]. Although not systematically studied, a direct or indirect role of mitochondria in microglial NLRP3 inflammasome activation seems plausible [64,65]. In support of a protective role of mitophagy in AD, a recent study using transgenic APP/PS1 and 3xTg-AD mice (APP Swedish, PSEN1 M146 V and MAPT P301 L mutations) reported that both amyloid-beta peptide and hyperphosphorylated tau inhibit mitophagy [66]. Pharmacological stimulation of mitophagy by urolithin A and actinonin prevented cognitive impairment and reduced NLRP3/ caspase-1-dependent neuroinflammation. A beneficial effect of selective autophagy on neuroinflammation linked to AD pathology was also shown in APP/PS1 mice with heterozygous loss of Beclin 1 expression. Beclin 1 is an essential component of the multiprotein complex required for nucleation of autophagic vesicles, and Beclin 1 expression was reported to be decreased in microglia isolated from AD patients [67]. APP/PS1 mice with reduced Beclin 1 expression showed increased levels of IL-1β, most likely caused by a decrease in NLRP3 degradation by autophagy [68]. However, in this mouse model amyloid-beta peptide levels or plaque size and distribution was not altered when compared to control mice. In addition to amyloid-beta peptide, aggregated tau has recently been shown to activate NLRP3 inflammasomes which in turn exacerbated tau pathology in a transgenic tau mouse model overexpressing human P301S tau [69]. Deletion of ASC in this mouse model of tauopathy was reported to reduce tau-induced pathology. In conclusion, sustained activation of the NLRP3 inflammasome induced by aggregated proteins seems to be a common mechanism driving inflammatory processes in neurodegenerative disease.

adaptive immune signaling via various receptors, such as the TNF receptor TNFR1, TRAIL receptor, IL-1 receptor, TLRs, NOD-like receptors, MAVS, RIG-I, CD40, CD95, and the T cell receptor (rev. in [42–45]). LUBAC has also been linked to the regulation of inflammasome activity. HOIL-1-deficient mice show a reduced secretion of IL-1β in response to NLRP3 stimulation and survive a lethal challenge with LPS, suggesting that linear ubiquitination contributes to NLRP3 inflammasome activation, presumably via linear ubiquitination of ASC [46]. Using macrophages from SHARPIN-deficient mice, SHARPIN was found critical for efficient NLRP3 inflammasome priming [47]. On the other hand, SHARPIN can inhibit caspase-1 activation in a LUBAC-independent manner [48,49], which may indicate a negative feedback loop. While the exact roles of A20 and LUBAC in NF-κB-dependent and -independent NLRP3 inflammasome priming and activation remain to be determined, it is interesting to note that mutations in A20 or LUBAC components are associated with autoinflammatory syndromes [50]. To add another layer of complexity, NF-κB signaling is implicated in both priming and activation of inflammasomes but also restricts inflammasome activation by promoting mitophagy [25]. Parkin as an E3 ubiquitin ligase influencing LUBAC activity, NF-κB signaling and mitophagy could modulate these processes in multiple ways, explaining inconsistent results from different models. Mitochondria not only contribute to inflammasome activation, they also seem to be a target of inflammasome-induced caspase-1 activation. Tiffany Horng and coworkers reported that NLRP3 inflammasomes damage mitochondria in a caspase-1-dependent manner, resulting in increased mitochondrial ROS production, dissipation of mitochondrial membrane potential and impairment of outer and inner membrane integrity [51]. This study suggested that caspase-1-mediated cleavage of Parkin is responsible for inhibition of mitophagy and increased mitochondrial damage in response to inflammasome activation. Mitochondrial damage and inhibition of mitophagy was also observed in a microglial model of NLRP3 inflammasome activation induced by human immunodeficiency virus type-1 (HIV) ssRNA40, which helps to explain neurotoxic and neuroinflammatory processes in HIV-infected patients [52]. 2.4. Mitochondria, NLRP3 inflammasomes and neurodegeneration The reciprocal relationship between mitochondria and inflammasomes may explain why several neurodegenerative diseases are associated with inflammasome activation (rev. in [53,54]). Beyond the reported role of Parkin in this interplay, several other findings suggest a link between inflammasomes and Parkinson's disease (PD). The neurotransmitter dopamine restricts NLRP3 inflammasome activation via the dopamine D1 receptor and formation of the second messenger cAMP [55]. In the study by Yan et al. cAMP was shown to bind to NLRP3 and to promote its ubiquitination by the E3 ubiquitin ligase MARCH7, inducing autophagosomal degradation of NLRP3. This mechanism not only suppresses NLRP3 inflammasome activation induced by the neurotoxin MPTP, an inhibitor of complex I of the respiratory chain that damages dopaminergic neurons, but also systemic inflammation induced by LPS. In addition, NLRP3 inflammasome activation was reported to stimulate aggregation of α-synuclein via caspase-1-mediated cleavage in neuroblastoma cells [56]. Supporting a role of caspase-1 activation in dopaminergic neuron degeneration, inhibition of caspase-1 decreased α-synuclein pathology and neuronal loss in a mouse model of multiple system atrophy, a synucleinopathy affecting oligodendroglia [57]. A recent study reported that activation of microglial NLRP3 inflammasomes is induced by fibrillar α-synuclein and other triggers of dopaminergic neurodegeneration, such as 6−OHDA treatment, in various PD mouse models [58]. In this study, also MitoPark mice were analyzed, in which dopaminergic neurodegeneration is induced by targeted inactivation of the mitochondrial transcription factor A (TFAM) gene in dopaminergic neurons [59]. Microglial NLRP3 inflammasome activation in MitoPark mice suggested

3. Mitochondria and the cGAS/STING pathway 3.1. Sensing of DNA by cGAS and activation of STING DNA has a high immunogenic potential, since it is sensed as a marker for infection or cellular damage inside and outside of cells. Extracellular DNA derived from pathogens, damaged cells or mitochondria is internalized and binds to TLR9 within the endosomal 4

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MPT that activates the cGAS/STING axis and promotes noncanonical NLRP3 inflammasome activation by caspase-4/-11 [102]. Tony WissCorey and coworkers reported that ganciclovir, an anti-viral drug, promotes a STING-dependent type I IFN response in microglia that mitigated inflammation in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE) [103]. Increased activation of the cGAS/STING pathway was recently linked to PD. Richard Youle and coworkers stressed Parkin- or PINK1-deficient mice by exhaustive exercise, a condition that was previously described to increase circulating nuclear DNA and expression of inflammatory cytokines [104–106]. In response to exhaustive exercise, serum levels of IL-6 and IFN-β1 were markedly increased in Parkin- or PINK1-deficient mice [107]. Since serum levels of IL-1β remained unchanged under these conditions, the authors speculated that not the NLRP3 inflammasome but rather the STING pathway was activated by exhaustive exercise in the absence of either Parkin or PINK1. In support of this notion, the deletion of STING expression in Parkin or PINK1 KO mice prevented the increase in circulating cytokines after exhaustive exercise. As another model of mitochondrial stress, Sliter et al. used mutator mice that express a proofreading-deficient mtDNA polymerase (PolG) and accumulate mtDNA mutations [108]. Parkin KO mice cross-bred with the mutator mice developed age-dependent dopaminergic neuron degeneration and locomotor symptoms [109], which were reverted by STING depletion in the study by Sliter et al. In both the acute (exhaustive exercise) and chronic model (PolG mutation) of mitochondrial stress, serum mtDNA levels were increased in the absence of either Parkin or PINK1, suggesting that impaired mitophagy is responsible for STING activation and inflammatory cytokine secretion in these models. Based on the fact that inflammation can occur as both a cause or consequence of neurodegenerative processes (rev. in [110–115]), this is an attractive hypothesis that raises interesting issues. First, what is the origin of mtDNA found in the serum of stressed Parkin- or PINK1-deficient mice and is serum mtDNA the only culprit responsible for STING activation? How can an increase in circulating mtDNA cause selective dopaminergic neurodegeneration? Is TLR9 signaling involved, which usually encounters circulating mtDNA? Which cell types are involved in mediating STING-dependent neurodegeneration? Is the inflammatory phenotype in these models causally related to an impairment of mitophagy? Notwithstanding the unsolved mechanism, it will be important in future studies to consider the role of innate immune processes in the pathogenesis of neurodegenerative diseases.

compartment [70]. TLR9 preferentially recognizes unmethylated CpGrich DNA, explaining why mtDNA is a powerful TLR9 activator. Signaling downstream of TLR9 results in IRF3 activation and type I IFN production as well as NF-κB and MAPK activation. A key sensor of cytoplasmic DNA is cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase), an enzyme that generates the second messenger 2′3′-cyclic GMP-AMP (cGAMP) upon engaging double-stranded (ds) DNA of viral, bacterial, nuclear or mitochondrial origin (rev. in [71–73]). Binding of DNA to cGAS induces the formation of liquid-like droplets by phase separation that increases cGAS enzymatic activity [74]. Interestingly, zinc ions promote DNAinduced phase separation and activation of cGAS and could contribute to efficient cGAS activation by mtDNA released from mitochondria, since the mitochondrial matrix stores zinc ions [75,76]. In addition, recent structural studies uncovered mechanistic details of DNA binding to cGAS and provided explanations for the preferential response of human cGAS to DNA fragments longer than 45 bp and for enhanced activation of cGAS by mtDNA bound to TFAM [77,78]. cGAMP formed by cGAS binds the ER-resident adaptor protein STING (stimulator of interferon genes) and causes conformational reorganization of STING [79,80]. As a consequence, STING traffics to an ER-Golgi intermediate compartment (ERGIC) and recruits and activates TBK1 (TANK-binding kinase 1). TBK1 phosphorylates STING, then phosphorylated STING recruits IRF3 for phosphorylation by TBK1. Phosphorylated IRF3 dimerizes, translocates to the nucleus and induces expression of type I IFNs. In addition, STING activates the IKK (IĸB kinase) complex, which phosphorylates IĸB (inhibitor of NF-ĸB). Subsequent ubiquitination targets IĸB to proteasomal degradation so that NF-ĸB heterodimers liberated from inhibitory binding to IĸB can translocate to the nucleus to induce expression of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF. Activation of MAP kinases and STAT (signal transducer and activator of transcription) transcription factors downstream of STING can also occur. Interestingly, STING has recently been reported to activate autophagy by a mechanism that is independent of TBK1 and IFN expression [81]. In this study, cGAMPinduced trafficking of STING to the ERGIC stimulated LC3 lipidation and autophagosome biogenesis that mediated the efficient clearance of cytosolic DNA and viruses. cGAS is activated by cytosolic dsDNA irrespective of its source and sequence, bearing the risk of autoinflammatory and autoimmune responses after access of nuclear DNA or mtDNA to the cytosol. Albeit prolonged and excessive cGAS/STING activation is associated with inflammation, this pathway plays a substantial role in cancer immunity by detecting micronuclei and cytoplasmic DNA fragments induced by chromosomal abnormalities or DNA damage [82–89].

4. Crosstalk between inflammasomes and cGAS Since mitochondria have the intrinsic potential to stimulate innate immune signaling pathways, the question emerges whether this feature is a consequence of inefficient immune tolerance to an organelle of bacterial ancestry or whether mitochondria are rather exploited to mount protective responses to intrinsic and extrinsic stress conditions. There are several examples supporting the view that via sensing of pathogen-induced mitochondrial damage, mitochondria contribute to effective immune responses. Cell type- and context-specific differences may govern a preferential cGAS/STING or inflammasome activation. Moreover, there is increasing evidence for a crosstalk between these pathways. Products of the inflammasome pathway, such as caspase-1 and gasdermin D, suppress cGAS/STING-mediated type I IFN production via cleavage of cGAS or potassium efflux, respectively [116–119]. On the other hand, the cGAS/STING pathway can boost inflammasome activation, for example via lysosomal cell death and potassium efflux upstream of NLRP3 [120].

3.2. Mitochondria, cGAS/STING, neuroinflammation and -degeneration Inappropriate activation of cGAS/STING by nuclear DNA or mtDNA has been linked to several diseases, such as systemic lupus erythematosus [90,91] and the rare autoinflammatory conditions AicardiGoutières syndrome and STING-associated vasculopathy with onset in infancy (SAVI) [92–97]. Sensing of extracellular DNA from dying cells upon myocardial infarction results in an inflammatory response implicated in pathological remodeling that is reduced by inhibiting the cGAS/STING pathway in mouse models of ischemic myocardial injury [98,99]. A study using mouse models of nonalcoholic steatohepatitis proposed that mtDNA from hepatocytes induces cGAS/STING signaling in Kupffer cells, thereby contributing to progression of this disease [100]. Recent studies indicated that the cGAS/STING pathway also plays a role in neuroinflammation. In a mouse model of traumatic brain injury, STING-deficient mice exhibited a decrease in both pro-inflammatory cytokine expression and lesion volume [101]. In cellular and mouse models of age-dependent macular degeneration with retinal pigmented epithelium cell death, Alu-retroelement RNA accumulation caused by deficiency of the RNase DICER1 leads to mtDNA release via

5. Mechanisms of mtDNA release mtDNA release can be induced by infectious pathogens but also by non-infectious mitochondrial stressors, for example by decreased expression of the mtDNA packaging protein TFAM [121], by Alu5

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Fig. 2. Possible mechanisms of mtDNA release. mtDNA can escape from damaged mitochondria via inner membrane extrusions through BAX/BAK pores, followed by inner membrane permeabilization. From these extrusions vesicles may pinch off. Other possibilities include transit of mtDNA through the mitochondrial permeability transition (MPT) pore or formation of mitochondriaderived vesicles (MDVs) that deliver mtDNA to the endosomal-lysosomal pathway or the plasma membrane.

retroelement RNA accumulation as a consequence of DICER1 deficiency [102], by cholesterol overload due to cholesterol-25-hydroxylase deficiency [122], by herpes simplex virus 1, Dengue virus and Mycobacterium tuberculosis [121,123,124]. Although various conditions can trigger mtDNA release from damaged mitochondria, little is known about the mechanism causing loss of mitochondrial inner membrane integrity (Fig. 2). Possible routes for mtDNA escape implicate the MPT pore and mitochondrial outer membrane permeabilization. Whereas apoptosis is usually an immunologically silent process, inhibition of caspases in apoptotic cells results in type I IFN expression and NF-κB activation [125–127]. Two recent studies on mitochondrial outer membrane permeabilization in caspase-independent cell death provided evidence for mtDNA release by inner membrane extrusions through Bax/Bak pores on the mitochondrial outer membrane [128,129]. Widening of Bax/Bak pores during apoptosis induces herniation of the inner membrane into the cytoplasm and mtDNA release upon inner membrane permeabilization. Another possibility would be an escape of mtDNA from the endosomallysosomal pathway upon uptake of extracellular mtDNA or an escape from autophagosomes after incomplete destruction of damaged mitochondria, although molecular mechanisms for these scenarios have not been provided so far. Another vehicle for mtDNA might be exosomes and mitochondria-derived vesicles that could deliver mtDNA to different cellular locales or mediate non-conventional secretion of mtDNA. 6. Conclusions and future directions The last decade has witnessed increasing insight into the pathomechanisms of neurodegenerative diseases, directing more attention towards inflammatory and innate immune responses. Mitochondria emerged as crucial organelles in the intricate interplay between neurodegeneration and neuroinflammation, since they serve as both a target and source of innate immune signaling. Inflammasomes and the cGAS/STING pathway are two major innate immune programs that can be activated by mitochondrial damage and have been linked to several 6

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