Targeting apoptosis in cancer therapy

Nature Reviews Clinical Oncology, Год журнала: 2020, Номер 17(7), С. 395 - 417

Опубликована: Март 23, 2020

Язык: Английский

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Mitochondria as multifaceted regulators of cell death

Nature Reviews Molecular Cell Biology, Год журнала: 2019, Номер 21(2), С. 85 - 100

Опубликована: Окт. 21, 2019

Язык: Английский

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Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

Nature Reviews Molecular Cell Biology, Год журнала: 2019, Номер 20(3), С. 175 - 193

Опубликована: Янв. 17, 2019

Язык: Английский

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The cGAS–STING pathway as a therapeutic target in inflammatory diseases

Nature reviews. Immunology, Год журнала: 2021, Номер 21(9), С. 548 - 569

Опубликована: Апрель 8, 2021

Язык: Английский

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TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

Cell, Год журнала: 2020, Номер 183(3), С. 636 - 649.e18

Опубликована: Окт. 1, 2020

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases amyotrophic lateral sclerosis (ALS), associated with neuroinflammatory cytokine profile related to upregulation nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when invades mitochondria releases via permeability transition pore. Pharmacologic inhibition or genetic deletion cGAS its downstream signaling partner STING prevents NF-κB IFN induced in pluripotent stem cell (iPSC)-derived motor neurons mutant mice. Finally, document elevated levels specific metabolite cGAMP spinal cord samples from patients, which may be biomarker mtDNA release cGAS/STING activation ALS. Our results identify as critical determinants TDP-43-associated pathology demonstrate potential targeting pathway

Язык: Английский

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Mitochondrial DNA in inflammation and immunity

EMBO Reports, Год журнала: 2020, Номер 21(4)

Опубликована: Март 23, 2020

Review23 March 2020Open Access Mitochondrial DNA in inflammation and immunity Joel S Riley Corresponding Author [email protected] orcid.org/0000-0001-9170-5716 Cancer Research UK Beatson Institute, Glasgow, Institute of Sciences, University Search for more papers by this author Stephen WG Tait orcid.org/0000-0001-7697-132X Information *,1,2 1Cancer 2Institute *Corresponding author. Tel: +44 141 330 6283; E-mail: 8703; EMBO Reports (2020)21:e49799https://doi.org/10.15252/embr.201949799 See the Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Mitochondria are cellular organelles that orchestrate a vast range biological processes, from energy production metabolism cell death inflammation. Despite seemingly symbiotic relationship, mitochondria harbour within them potent agonist innate immunity: their own genome. Release mitochondrial into cytoplasm out extracellular milieu activates plethora different pattern recognition receptors immune responses, including cGAS-STING, TLR9 inflammasome formation leading to, among others, robust type I interferon responses. In Review, we discuss how mtDNA can be released mitochondria, various inflammatory pathways triggered release its myriad consequences health disease. 5hmC 5-Hydroxymethylcytosine 5mC 5-Methylcytosine AGS Aicardi–Goutieres syndrome AIM2 Absent melanoma 2 APC Antigen-presenting ASC Apoptosis-associated speck-like protein containing CARD ATP Adenosine triphosphate BAK Bcl-2 homologous antagonist/killer BAX Bcl-2-associated X BID BH3 interacting-domain Caspase activation recruitment domain CD47 Cluster differentiation 47 CDN Cyclic dinucleotide cGAMP guanosine monophosphate–adenosine monophosphate cGAS GMP-AMP synthase CLR C-type lectin receptor CMPK2 Cytidine/Uridine kinase DAMP Damage-associated molecular DC Dendritic DNase Deoxyribonuclease dsDNA Double-stranded ER Endoplasmic reticulum EV Extracellular vesicle GTP Guanosine-5′-triphosphate HMGB1 High-mobility group 1 HSV-1 Herpes simplex virus-1 IAP Inhibitor apoptosis IFNAR Interferon-α/β IFN-β Interferon-β IFN-γ Interferon-γ IL-18 Interleukin-18 IL-1R Interleukin-1 IL-1β Interleukin-1β IL-6 Interleukin-6 IRF3 Interferon regulatory factor 3 ISG Interferon-stimulated gene K+ Potassium LPS Lipopolysaccharide LRR Leucine-rich repeat MAPK Mitogen-activated MAVS anti-viral signalling MDA5 Melanoma differentiation-associated 5 MEF Mouse embryonic fibroblast MiDAS dysfunction-associated senescence MI Myocardial infarction MOMP outer membrane permeabilisation mPTP permeability transition pore NASH Non-alcoholic fatty liver disease NET Neutrophil trap NF-κB Nuclear kappa-light-chain-enhancer activated B cells NLRC4 NLR Family Domain Containing 4 Nucleotide oligomerisation domain-like NLRP1 Pyrin NLRP3 NACHT, PYD domain-containing NOD ODN Oligodeoxynucleotide OPA1 Optic Atrophy Dynamin Like GTPase PAMP Pathogen-associated pDC Plasmacytoid dendritic PD-L1 Programmed death-ligand PINK1 Phosphatase tensin homolog-induced PMA Phorbol 12-myristate 13-acetate PNPase Polynucleotide phosphorylase PRR Pattern RAGE Receptor advanced glycation endproducts RIG-I Retinoic acid-inducible RIP1 Receptor-interacting serine/threonine-protein RLR gene-I-like RNP IC Ribonucleotide complex ROS Reactive oxygen species SAMDH1 Sterile alpha motif HD SIRS Systemic response SLE lupus erythematosus ssDNA Single-stranded STING Stimulator genes SUV3 Suppressor Var1 TBK1 TANK-binding TFAM Transcription A, Toll-like 9 TLR TNF Tumour necrosis TREX1 Three Prime Repair Exonuclease tRNA Transfer RNA VDAC Voltage-dependent anion channel Introduction Serving as first line defence, system guards us against insults invading microorganisms. Infection pathogenic agents is detected (PRRs) which recognise specific pathogen-associated patterns (PAMPs). PRRs broadly classified four distinct groups: NOD-like (NLRs), (TLRs), retinoic gene-I (RIG-I)-like (RLRs) (CLRs) 1. Upon detection PAMP, initiate multitude pathways, culminate up-regulation interferons, pro-inflammatory chemokines cytokines. These prime adaptive create hostile environment microorganism survive. Additionally, damage-associated (DAMPs) triggers arise itself, such proteins or DNA, activate 2. appeared eukaryotic about two billion years ago α-proteobacterium, what thought an endosymbiotic relationship 3, 4. Over time, these bacteria evolved become much-studied organelle know today, playing crucial roles metabolism, calcium homeostasis death. Nevertheless, they have maintained independent genome, encodes 37 genes, comprised 13 mRNAs forming key components oxidative phosphorylation system, addition ribosomal 22 tRNAs An estimated 1,000 located all which, except those encoded mtDNA, translated cytosol imported 5. itself circular molecule double-stranded (ds)DNA. both heavy light strand results long, full-length transcripts processed RNase enzymes produce mature mRNA, RNA. mammals, polymerase responsible replication γ, but POLγ cannot replicate dsDNA, helicase Twinkle required act directly before unwind structure. Newly synthesised single-stranded (ss)DNA bound DNA-binding prevent secondary structure attack nucleases. has recently been reviewed extensively elsewhere 6; here, focus on unique aspects make it immunostimulatory. We will then ejected under circumstances cGAS-STING signalling, inflammasomes receptors. also role neutrophil traps (NETs) transfer between cells. stimulator Potentially stemming bacterial origin, sensed "foreign", suggesting seen differently "self" One example methylation status, where many studies reported hypomethylated compared nuclear 7, 8, despite presence methyltransferases 9, 10. Some groups aberrant 5-methylcytosine (5mC) 5-hydroxymethylcytosine (5hmC) at CpG motifs 9-14, although others proposed technical limitations work using sensitive techniques report devoid 15. Clearly, effort determining precise degree if showing absence correct, would unmethylated similar could potentially TLR9, absent (AIM2) 15-18. transcription may represent rich source potential activators receptors; example, RNA:DNA hybrids form during transcription, long stretches R-loops composed with non-template recognised 16. exists matrix close proximity electron transport chain, major reactive species. Due this, particularly vulnerable oxidation, resulting mutations contribute pathogenesis cancer 17, diabetes 18 ageing 19. It was had limited capacity repair mtDNA; however, multiple now well characterised 20. often schematically represented plasmid structure; over-simplification. Rather, super-resolution imaging revealed densely compacted nucleoids consisting one copy number 21, most notable A (mtTFA, commonly referred TFAM). might assumed compaction structures shields recognition, not case shall further fact, shown immunostimulatory 13, 14. landmark study 2004, Collins et al found injecting joints mice resulted localised arthritis. Further investigation dependent oxidatively damaged bases injection oligodeoxynucleotide (ODN) same sequence without oxidised residue no effect. The observation elicit responses opened whole new field research, appreciated stimulate PRRs, cGAS, (Fig 1). subsequent occurs infection, neurodegeneration, rest Review. Figure Overview engaged DNAMitochondrial (mtDNA) trigger endosomal via cytosolic (AIM2 NLRP3). Top: binds endosome eliciting NF-κB-dependent program. Middle: recognises endoplasmic (ER)-localised triggering response. Bottom: mtDNA-dependent activity leads caspase-1-dependent maturation IL-1 IL-8. Download figure PowerPoint infection Through necessity, elegant systems detect DNA. (cGAS) direct detector, dimer 23, 24. undergoes conformational change facilitates conversion 2′3′-cyclic (cGAMP) 25-31. second messenger, (ER)-resident (STING) inducing C-terminal tail. (TBK1) recruited phosphorylates (IRF3), hundreds stimulatory (ISGs) potently 32 2). primarily avoid persistent self-DNA nucleus, recent present nucleus 33, 34 plasma 35. attempt resolve discrepancies Volkmann 36 reveals model than sensing paradigm. authors show majority nuclear, propose must "desequestered" prior full activation. However, remains unclear tethered compartment. were able 37-39. White Rongvaux explored context (discussed later Review), whereas West provided evidence deficiency promotes stress mis-packaged ejection bind initiating 39 Of pathophysiological relevance, (HSV-1) vesicular stomatitis virus (VSV) stress, depletion entrance cytoplasm. cytoplasmic conferring state cell. Importantly, Tfam+/− cells, exhibit resistant VSV wild-type heightened expression owing release. Mechanistically, nuclease, UL12.5, localises degrades complete loss infected 40, 41. Removal does appear impact HSV 42. Furthermore, exonuclease effective viral maintain cell-to-cell infectivity, though whether related UL12.5's mtDNA-targeted nuclease unknown 43. signallingVarious stresses lead Alternatively, (MOMP) Once cytoplasmic, catalyses messenger 2′3′ cyclic GMP–AMP (2′3′cGAMP) GTP. adaptor kinase. Active Curiously, viruses, dengue virus, elicits response, being DNA-specific 44. Several causes predominantly cytosol, 45, 46 47. Dengue strategies circumvent mtDNA-induced encoding proteases target degradation, thus ensuring persistence 46, 48, 49. pathogen Mycobacterium tuberculosis IRF3-dependent 50-52. This solely due mycobacterium other identified ensuing 53. strain-dependent dynamics M. tuberculosis-induced mtDNA. Previous observed cytochrome c tuberculosis, indicating there possible BAX/BAK-dependent detail later) infection-related 54 Pathogen-infected secrete Aarreberg discovers link secretion cGAS-STING-dependent surrounding bystander Interestingly, stimulation increases mass, decreases induces 55. detectable death, mechanism release, rule (see below). time implicated cell-intrinsic defence 56-58, suggest plays initiation During programmed pro-apoptotic permeabilise allow passage molecules move inner space caspase cascade, rapid 59. showed apoptotic activation, promiscuous manner, vivo mildly elevated levels blood, level sufficient induce interferon-stimulated 37, 38 3). suggests caspases play dampening dying maintaining "immune-silent" nature cleave (MAVS), 60, supporting notion dampen High-resolution expanded our understanding membrane, inhibition pores grow dramatically, herniation extrusion 61-63 caspase-inhibited conditions, down-regulation inhibitor (IAPs), NF-κB-inducing (NIK) transcriptional program, release-induced 64. cytokines up-regulated after serve promote macrophage 64, 65. anti-tumour effects, highlighting therapeutic treatment Collectively, help reconcile unresolved questions remain. Firstly, regulated process, so, how? size small ions minutes 61, insufficient nucleoid probably only transient, 66-69. Secondly, differences permeabilisation, varying degrees 62, implying factors permeabilisation. Finally, physiological relevance death-related unknown. Most types undergo caspase-dependent vivo, presumably limiting any mtDNA-driven some types, instance cardiomyocytes, display deficient downstream 70. Such generate greater healthy serving "early warning" instructing transcribe important survival 4) 71, 72. 3. inflammationFollowing enables caspase-activating intermembrane space. Following macropores causing membrane. (dsRNA) released. Collective MAVS, NF-κB. anti-inflammatory, part, through cleavage inactivation molecules. Non-cell autonomous effects mtDNA(A) encounter, neutrophils extrude (both mitochondrial) forms microbes. properties, pathological diseases lupus. (B) exosomes intact neighbouring impacting recipient Inflammatory non-cell effects. cGAS-induced gap junctions possess dsRNA known immunogenic 73. arises lights strands rapidly degraded not, nearly origin. polynucleotide accumulation dsRNA, when depleted, accumulates driven 74. Silencing suppresses strongly escape 74 patients decrease PNPT1, protein, serum event, spreading BAX/BAK pores, culminating conditions sub-lethal called minority MOMP, genomic instability transformation 75. Brokatsky invasion machinery 76. study, pathogens nevertheless can, (presumably pores), stimulating cytokine How else mitochondria? Another (mPTP) 77, 78. exact composition unclear, seems consensus cyclophilin D 79. spans high concentration stresses. predicted efflux smaller 1.5 kDa, much 80, 81. fragments pass 82, 83. sustained opening swelling rupture permit involvement ruled chitosan, vaccine adjuvant, appears cGAS-STING- mPTP-dependent possibly rigorously assessed 84. intriguing experiencing caused lack endonuclease G formed oligomers voltage-dependent (VDAC) 85. As 86, 87, tested lupus-like Using VDAC1 VBIT-4, reduce symptoms lupus-prone mice, providing rationale VDAC-mediated Therapeutic targeting There currently intense interest development inhibitors pathway, depending humans, systemic Aicardi–Goutières (AGS) involved 88. For TREX1, exonuclease, frequently mutated human (SLE) 89-91, co-deletion STING, (IFNAR) rescues phenotype 92-98. Accumulation defining characteristic SLE, deletions DNA- RNA-related SAMDH1, RnaseH2 frequent 99-102. Gain-of-function 103, 104. II humans autoinflammation increased IFN 105 arthritis 106. degradation dead engulfed macrophages 98, 106, 107, 108, 109 contribution TLRs 108. (MI) another condition involve strong component. King 110 ischaemic engulfment drives Genetic pharmacological disruption improved outcomes post-MI, proposing axis suitable intervention 110, 111. While clear per se, heart 112-114. inhibiting pathway settings beneficial patients. Small 115, 116 117 developed, antag

Язык: Английский

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Mitochondrial control of inflammation

Nature reviews. Immunology, Год журнала: 2022, Номер 23(3), С. 159 - 173

Опубликована: Июль 25, 2022

Язык: Английский

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Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance

Theranostics, Год журнала: 2020, Номер 11(4), С. 1845 - 1863

Опубликована: Дек. 16, 2020

Aims: Ischemia-reperfusion injury (IRI)-induced acute kidney (IRI-AKI) is characterized by elevated levels of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation, but the potential link among these features remains unclear. In this study, we aimed to investigate specific role ROS (mtROS) in initiating DNA (mtDNA) damage inflammation during IRI-AKI. Methods: The changes renal function, IRI-AKI mice with or without mtROS inhibition were analyzed vivo. impact on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, respiration, cytokine release was tubular cells vitro. effects knockdown also Finally, mtDNA nucleoids measured samples from patients. Results: Decreasing attenuated damage, mice. reversed decrease copy number that occurs HK2 under oxidative stress. reduced abundance suppressing its promoting Lon-mediated degradation. Silencing abolished Mito-Tempo (MT)-induced rescue function Loss found kidneys AKI Conclusion: can promote TFAM-mediated maintenance, resulting decreased energy metabolism increased release. defects may be a promising target for repair after

Язык: Английский

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VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

Science, Год журнала: 2019, Номер 366(6472), С. 1531 - 1536

Опубликована: Дек. 20, 2019

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering type Ι interferon (IFN) response. outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little known about its role live cells. We found that oxidatively stressed mitochondria release short fragments via pores formed by voltage-dependent anion channel (VDAC) oligomers membrane. Furthermore, positively charged residues N-terminal domain of VDAC1 interact with mtDNA, promoting oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases IFN signaling, neutrophil extracellular traps, and disease severity a mouse model systemic lupus erythematosus. Thus, inhibiting potential therapeutic approach diseases associated release.

Язык: Английский

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The Coming Decade of Cell Death Research: Five Riddles

Cell, Год журнала: 2019, Номер 177(5), С. 1094 - 1107

Опубликована: Май 1, 2019

Язык: Английский

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