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Cytosolic Escape of Mitochondrial DNA Triggers cGAS-STING Pathway-Dependent Neuronal PANoptosis in Response to Intermittent Hypoxia

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Abstract

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA.

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No datasets were generated or analysed during the current study.

References

  1. Jordan AS, McSharry DG, Malhotra A (2014) Adult obstructive sleep apnoea. Lancet 383:736–747

    Article  PubMed  Google Scholar 

  2. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP (2010) Pathophysiology of sleep apnea. Physiol Rev 90:47–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lavie P, Herer P, Hoffstein V (2000) Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 320:479–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Idris I, Hall AP, O’Reilly J, Barnett A, Allen M, Andrews R, Grunstein P, Lewis K, Goenka N, Wilding JP (2009) Obstructive sleep apnoea in patients with type 2 diabetes: aetiology and implications for clinical care. Diabetes Obes Metab 11:733–741

    Article  PubMed  Google Scholar 

  5. Tasali E, Mokhlesi B, Van Cauter E (2008) Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest 133:496–506

    Article  PubMed  Google Scholar 

  6. Yacoub M, Youssef I, Salifu MO, McFarlane SI (2017) Cardiovascular Disease Risk in Obstructive Sleep apnea: an update. J Sleep Disord Ther 7:283

    PubMed  Google Scholar 

  7. Han Q, Li G, Ip MS, Zhang Y, Zhen Z, Mak JC, Zhang N (2018) Haemin attenuates intermittent hypoxia-induced cardiac injury via inhibiting mitochondrial fission. J Cell Mol Med 22:2717–2726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wallace A, Bucks RS (2013) Memory and obstructive sleep apnea: a meta-analysis. Sleep 36:203–220

    PubMed  PubMed Central  Google Scholar 

  9. Jackson ML, Howard ME, Barnes M (2011) Cognition and daytime functioning in sleep-related breathing disorders. Prog Brain Res 190:53–68

    Article  PubMed  Google Scholar 

  10. Macey KE, Macey PM, Woo MA, Henderson LA, Frysinger RC, Harper RK, Alger JR, Yan-Go F, Harper RM (2006) Inspiratory loading elicits aberrant fMRI signal changes in obstructive sleep apnea. Respir Physiol Neurobiol 151:44–60

    Article  PubMed  Google Scholar 

  11. Macey PM, Harper RM (2005) OSA brain morphology differences: magnitude of loss approximates age-related effects. Am J Respir Crit Care Med 172:1056–1057 author reply 1057–1058

    Article  CAS  PubMed  Google Scholar 

  12. Woo MA, Macey PM, Keens PT, Kumar R, Fonarow GC, Hamilton MA, Harper RM (2005) Functional abnormalities in brain areas that mediate autonomic nervous system control in advanced heart failure. J Card Fail 11:437–446

    Article  PubMed  Google Scholar 

  13. Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, Luo C, Kheirandish L, Gozal D, Liu R (2004) Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience 126:313–323

    Article  CAS  PubMed  Google Scholar 

  14. Shan X, Chi L, Ke Y, Luo C, Qian S, Gozal D, Liu R (2007) Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage. Neurobiol Dis 28:206–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Si J, Liu B, Qi K, Chen X, Li D, Yang S, Ji E (2023) Tanshinone IIA inhibited intermittent hypoxia induced neuronal injury through promoting autophagy via AMPK-mTOR signaling pathway. J Ethnopharmacol 315:116677

    Article  CAS  PubMed  Google Scholar 

  16. Zhan G, Fenik P, Pratico D, Veasey SC (2005) Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury. Am J Respir Crit Care Med 171:1414–1420

    Article  PubMed  PubMed Central  Google Scholar 

  17. Baker TL, Fuller DD, Zabka AG, Mitchell GS (2001) Respiratory plasticity: differential actions of continuous and episodic hypoxia and hypercapnia. Respir Physiol 129:25–35

    Article  CAS  PubMed  Google Scholar 

  18. Macey PM, Sarma MK, Nagarajan R, Aysola R, Siegel JM, Harper RM, Thomas MA (2016) Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex. J Sleep Res 25:390–394

    Article  PubMed  PubMed Central  Google Scholar 

  19. Eisele HJ, Markart P, Schulz R (2015) Obstructive Sleep Apnea, Oxidative Stress, and Cardiovascular Disease: Evidence from Human Studies. Oxid Med Cell Longev 2015:608438

  20. Vakulin A, Green MA, D’Rozario AL, Stevens D, Openshaw H, Bartlett D, Wong K, McEvoy RD, Grunstein RR, Rae CD (2022) Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea. J Sleep Res 31:e13482

    Article  PubMed  Google Scholar 

  21. Ryan S, McNicholas WT, Taylor CT (2007) A critical role for p38 map kinase in NF-kappaB signaling during intermittent hypoxia/reoxygenation. Biochem Biophys Res Commun 355:728–733

    Article  CAS  PubMed  Google Scholar 

  22. Deng Y, Liu K, Pan Y, Ren J, Shang J, Chen L, Liu H (2020) TLR2 antagonism attenuates the hippocampal neuronal damage in a murine model of sleep apnea via inhibiting neuroinflammation and oxidative stress. Sleep Breath 24:1613–1621

    Article  PubMed  Google Scholar 

  23. Zhang P, Wang Y, Wang H, Cao J (2021) Sesamol alleviates chronic intermittent hypoxia-induced cognitive deficits via inhibiting oxidative stress and inflammation in rats. NeuroReport 32:105–111

    Article  CAS  PubMed  Google Scholar 

  24. Douglas RM, Ryu J, Kanaan A, Del Carmen Rivero M, Dugan LL, Haddad GG, Ali SS (2010) Neuronal death during combined intermittent hypoxia/hypercapnia is due to mitochondrial dysfunction. Am J Physiol Cell Physiol 298:C1594–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moya GE, Rivera PD, Dittenhafer-Reed KE (2021) Evidence for the role of mitochondrial DNA release in the inflammatory response in neurological disorders. Int J Mol Sci 22

  26. Li W, Yang S, Yu FY, Zhao Y, Sun ZM, An JR, Ji E (2018) Hydrogen ameliorates chronic intermittent hypoxia-induced neurocognitive impairment via inhibiting oxidative stress. Brain Res Bull 143:225–233

    Article  CAS  PubMed  Google Scholar 

  27. Sharma C, Kim S, Nam Y, Jung UJ, Kim SR (2021) Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s Disease. Int J Mol Sci 22:4850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ma XM, Geng K, Law BY, Wang P, Pu YL, Chen Q, Xu HW, Tan XZ, Jiang ZZ, Xu Y (2023) Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes. Cell Biol Toxicol 39:277–299

    Article  CAS  PubMed  Google Scholar 

  29. Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL (2020) TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell 183:636–649 e618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim J, Kim HS, Chung JH (2023) Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway. Exp Mol Med 55:510–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xu J, Li Q, Xu CY, Mao S, ** JJ, Gu W, Shi Y, Zou CF, Ye L (2022) Obstructive sleep apnea aggravates neuroinflammation and pyroptosis in early brain injury following subarachnoid hemorrhage via ASC/HIF-1alpha pathway. Neural Regen Res 17:2537–2543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guo X, Shi Y, Du P, Wang J, Han Y, Sun B, Feng J (2019) HMGB1/TLR4 promotes apoptosis and reduces autophagy of hippocampal neurons in diabetes combined with OSA. Life Sci 239:117020

    Article  CAS  PubMed  Google Scholar 

  33. Zhang H, Zhou L, Zhou Y, Wang L, Jiang W, Liu L, Yue S, Zheng P, Liu H (2021) Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFkappaB signaling pathway. Life Sci 285:119963

    Article  CAS  PubMed  Google Scholar 

  34. Samir P, Malireddi RKS, Kanneganti TD (2020) The PANoptosome: a deadly protein complex driving pyroptosis, apoptosis, and necroptosis (PANoptosis). Front Cell Infect Microbiol 10:238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee S, Karki R, Wang Y, Nguyen LN, Kalathur RC, Kanneganti TD (2021) AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence. Nature 597:415–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sundaram B, Pandian N, Mall R, Wang Y, Sarkar R, Kim HJ, Malireddi RKS, Karki R, Janke LJ, Vogel P, Kanneganti TD (2023) NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs. Cell 186:2783–2801 e2720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng M, Kanneganti TD (2020) The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis). Immunol Rev 297:26–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Malireddi RKS, Kesavardhana S, Kanneganti TD (2019) ZBP1 and TAK1: Master regulators of NLRP3 Inflammasome/Pyroptosis, apoptosis, and necroptosis (PAN-optosis). Front Cell Infect Microbiol 9:406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Christgen S, Zheng M, Kesavardhana S, Karki R, Malireddi RKS, Banoth B, Place DE, Briard B, Sharma BR, Tuladhar S, Samir P, Burton A, Kanneganti TD (2020) Identification of the PANoptosome: a molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis). Front Cell Infect Microbiol 10:237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu LH, **e H, Shi ZH, Du LD, Wing YK, Li AM, Ke Y, Yung WH (2015) Critical role of endoplasmic reticulum stress in Chronic Intermittent Hypoxia-Induced deficits in synaptic plasticity and long-term memory. Antioxid Redox Signal 23:695–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. ** W, Zhao J, Yang E, Wang Y, Wang Q, Wu Y, Tong F, Tan Y, Zhou J, Kang C (2022) Neuronal STAT3/HIF-1alpha/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A. Theranostics 12:3196–3216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Seibenhener ML, Wooten MW (2012) Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp

  43. Oorschot DE, Jones DG (1986) Effect of cytosine arabinoside on the composition of the nonneuronal cell population in cerebral explants. Exp Neurol 92:404–412

    Article  CAS  PubMed  Google Scholar 

  44. Aminova LR, Chavez JC, Lee J, Ryu H, Kung A, Lamanna JC, Ratan RR (2005) Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line. J Biol Chem 280:3996–4003

    Article  CAS  PubMed  Google Scholar 

  45. Zhang Y, Miao Y, **ong X, Tan J, Han Z, Chen F, Lei P, Zhang Q (2023) Microglial exosomes alleviate intermittent hypoxia-induced cognitive deficits by suppressing NLRP3 inflammasome. Biol Direct 18:29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  47. Ouyang W, Wang S, Yan D, Wu J, Zhang Y, Li W, Hu J, Liu Z (2023) The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation. Signal Transduct Target Ther 8:371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Phillips NR, Sprouse ML, Roby RK (2014) Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: a multiplex real-time PCR assay. Sci Rep 4:3887

    Article  PubMed  PubMed Central  Google Scholar 

  49. Guo Y, Gu R, Gan D, Hu F, Li G, Xu G (2020) Mitochondrial DNA drives noncanonical inflammation activation via cGAS-STING signaling pathway in retinal microvascular endothelial cells. Cell Commun Signal 18:172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shi G, Liu L, Cao Y, Ma G, Zhu Y, Xu J, Zhang X, Li T, Mi L, Jia H, Zhang Y, Liu X, Zhou Y, Li S, Yang G, Liu X, Chen F, Wang B, Deng Q, Zhang S, Zhang J (2023) Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1alpha/ASK1/JNK signaling pathway in mice with traumatic brain injury. J Neuroinflammation 20:222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Digilio L, Yap CC, Winckler B (2015) Ctip2-, Satb2-, Prox1-, and GAD65-Expressing neurons in rat cultures: preponderance of single- and double-positive cells, and cell type-specific expression of Neuron-Specific Gene Family members, Nsg-1 (NEEP21) and Nsg-2 (P19). PLoS ONE 10:e0140010

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ma J, Yang Q, Wei Y, Yang Y, Ji C, Hu X, Mai S, Kuang S, Tian X, Luo Y, Liang G, Yang J (2016) Effect of the PGD2-DP signaling pathway on primary cultured rat hippocampal neuron injury caused by aluminum overload. Sci Rep 6:24646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Perycz M, Urbanska AS, Krawczyk PS, Parobczak K, Jaworski J (2011) Zipcode binding protein 1 regulates the development of dendritic arbors in hippocampal neurons. J Neurosci 31:5271–5285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Casella EM, Thomas TC, Vanino DL, Fellows-Mayle W, Lifshitz J, Card JP, Adelson PD (2014) Traumatic brain injury alters long-term hippocampal neuron morphology in juvenile, but not immature, rats. Childs Nerv Syst 30:1333–1342

    Article  PubMed  Google Scholar 

  55. Messaoud-Nacer Y, Culerier E, Rose S, Maillet I, Rouxel N, Briault S, Ryffel B, Quesniaux VFJ, Togbe D (2022) STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS). Cell Death Dis 13:269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yan YR, Zhang L, Lin YN, Sun XW, Ding YJ, Li N, Li HP, Li SQ, Zhou JP, Li QY (2021) Chronic intermittent hypoxia-induced mitochondrial dysfunction mediates endothelial injury via the TXNIP/NLRP3/IL-1beta signaling pathway. Free Radic Biol Med 165:401–410

    Article  CAS  PubMed  Google Scholar 

  57. Smith JA (2020) STING, the endoplasmic reticulum, and Mitochondria: is three a crowd or a conversation? Front Immunol 11:611347

    Article  CAS  PubMed  Google Scholar 

  58. Cao Y, Shi M, Liu L, Zuo Y, Jia H, Min X, Liu X, Chen Z, Zhou Y, Li S, Yang G, Liu X, Deng Q, Chen F, Chen X, Zhang S, Zhang J (2023) Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1alpha pathway after traumatic brain injury in mice. Front Immunol 14:1125759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhu Y, Tang Q, Wang G, Han R (2017) Tanshinone IIA protects hippocampal neuronal cells from reactive oxygen species through changes in Autophagy and activation of phosphatidylinositol 3-Kinase, protein Kinas B, and mechanistic target of Rapamycin pathways. Curr Neurovasc Res 14:132–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Klenke S, Specking C, Stegen M, Engler A, Peters J (2020) Methylation in HT22 cells and primary hippocampal neurons with and without isoflurane exposurewhether isoflurane causes. BMC Anesthesiol 20:66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lim J, Bang Y, Kim KM, Choi HJ (2022) Differentiated HT22 cells as a novel model for in vitro screening of serotonin reuptake inhibitors. Front Pharmacol 13:1062650

    Article  CAS  PubMed  Google Scholar 

  62. Hou Y, Zhang Y, Jiang S, **e N, Zhang Y, Meng X, Wang X (2023) Salidroside intensifies mitochondrial function of CoCl(2)-damaged HT22 cells by stimulating PI3K-AKT-MAPK signaling pathway. Phytomedicine 109:154568

    Article  CAS  PubMed  Google Scholar 

  63. Chen S, Zou Q, Guo Q, Chen Y, Kuang X, Zhang Y, Liu Y, Wu W, Li G, Tu L, Tong J, Li S, Ma L, Li Q (2020) SPARC Knockdown reduces Glutamate-Induced HT22 hippocampal nerve cell damage by regulating Autophagy. Front Neurosci 14:581441

    Article  PubMed  Google Scholar 

  64. Liu Y, Tan J, Miao Y, Zhang Q (2024) Neurogenesis, a potential target for intermittent hypoxia leading to Cognitive decline. Curr Stem Cell Res Ther 19:63–70

    Article  CAS  PubMed  Google Scholar 

  65. Kerner NA, Roose SP (2016) Obstructive sleep apnea is linked to Depression and Cognitive Impairment: evidence and potential mechanisms. Am J Geriatr Psychiatry 24:496–508

    Article  PubMed  PubMed Central  Google Scholar 

  66. Song S, Tan J, Miao Y, Zhang Q (2017) Effect of different levels of intermittent hypoxia on autophagy of hippocampal neurons. Sleep Breath 21:791–798

    Article  PubMed  Google Scholar 

  67. He Q, Yang QC, Zhou Q, Zhu H, Niu WY, Feng J, Wang Y, Cao J, Chen BY (2014) Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. PLoS ONE 9:e86326

    Article  PubMed  PubMed Central  Google Scholar 

  68. Bertheloot D, Latz E, Franklin BS (2021) Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol Immunol 18:1106–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, Mattson MP, Croteau DL, Bohr VA (2021) NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci U S A 118:e2011226118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ (2018) Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen C, Xu P (2023) Cellular functions of cGAS-STING signaling. Trends Cell Biol 33:630–648

    Article  CAS  PubMed  Google Scholar 

  72. Liao Y, Cheng J, Kong X, Li S, Li X, Zhang M, Zhang H, Yang T, Dong Y, Li J, Xu Y, Yuan Z (2020) HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway. Theranostics 10:9644–9662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jiang GL, Yang XL, Zhou HJ, Long J, Liu B, Zhang LM, Lu D (2021) cGAS knockdown promotes microglial M2 polarization to alleviate neuroinflammation by inhibiting cGAS-STING signaling pathway in cerebral ischemic stroke. Brain Res Bull 171:183–195

    Article  CAS  PubMed  Google Scholar 

  74. Kong L, Li W, Chang E, Wang W, Shen N, Xu X, Wang X, Zhang Y, Sun W, Hu W, Xu P, Liu X (2022) mtDNA-STING Axis mediates microglial polarization via IRF3/NF-κB signaling after ischemic stroke. Front Immunol 13:860977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu M, Li Y, Han S, Wang H, Li J (2023) Activin a alleviates neuronal injury through inhibiting cGAS-STING-mediated autophagy in mice with ischemic stroke. J Cereb Blood Flow Metab 43:736–748

    Article  CAS  PubMed  Google Scholar 

  76. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L (2023) Mitochondrial control of inflammation. Nat Rev Immunol 23:159–173

    Article  CAS  PubMed  Google Scholar 

  77. Shen K, Pender CL, Bar-Ziv R, Zhang H, Wickham K, Willey E, Durieux J, Ahmad Q, Dillin A (2022) Mitochondria as Cellular and Organismal Signaling hubs. Annu Rev Cell Dev Biol 38:179–218

    Article  CAS  PubMed  Google Scholar 

  78. Shi M, Chen F, Chen Z, Yang W, Yue S, Zhang J, Chen X (2021) Sigma-1 receptor: a potential therapeutic target for traumatic brain Injury. Front Cell Neurosci 15:685201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shang F, Wang SC, Gongol B, Han SY, Cho Y, Schiavon CR, Chen L, **ng Y, Zhao Y, Ning M, Guo X, He F, Lei Y, Wang L, Manor U, Marin T, Chou KT, He M, Huang PH, Shyy JY, Malhotra A (2023) Obstructive sleep apnea-induced endothelial dysfunction is mediated by miR-210. Am J Respir Crit Care Med 207:323–335

    Article  CAS  PubMed  Google Scholar 

  80. Laouafa S, Roussel D, Marcouiller F, Soliz J, Gozal D, Bairam A, Joseph V (2019) Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats. Acta Physiol (Oxf) 226:e13255

    Article  PubMed  Google Scholar 

  81. Hopfner KP, Hornung V (2020) Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol 21:501–521

    Article  CAS  PubMed  Google Scholar 

  82. Paul BD, Snyder SH, Bohr VA (2021) Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and aging. Trends Neurosci 44:83–96

    Article  CAS  PubMed  Google Scholar 

  83. Bi X, Du C, Wang X, Wang XY, Han W, Wang Y, Qiao Y, Zhu Y, Ran L, Liu Y, **ong J, Huang Y, Liu M, Liu C, Zeng C, Wang J, Yang K, Zhao J (2021) Mitochondrial damage-Induced Innate Immune activation in vascular smooth muscle cells promotes chronic kidney Disease-Associated Plaque vulnerability. Adv Sci (Weinh) 8:2002738

    Article  CAS  PubMed  Google Scholar 

  84. Huang LS, Hong Z, Wu W, **ong S, Zhong M, Gao X, Rehman J, Malik AB (2020) mtDNA activates cGAS Signaling and suppresses the YAP-Mediated endothelial cell Proliferation Program to Promote Inflammatory Injury. Immunity 52:475–486 e475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu Z, Wang M, Wang X, Bu Q, Wang Q, Su W, Li L, Zhou H, Lu L (2022) XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury. Redox Biol 52:102305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang W, Li G, Luo R, Lei J, Song Y, Wang B, Ma L, Liao Z, Ke W, Liu H, Hua W, Zhao K, Feng X, Wu X, Zhang Y, Wang K, Yang C (2022) Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis. Exp Mol Med 54:129–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang Q, Wei J, Liu Z, Huang X, Sun M, Lai W, Chen Z, Wu J, Chen Y, Guo X, Huang Q (2022) STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice. Redox Biol 54:102367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang X, Wu J, Liu Q, Li X, Li S, Chen J, Hong Z, Wu X, Zhao Y, Ren J (2020) mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion. Cell Death Dis 11:1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ding R, Li H, Liu Y, Ou W, Zhang X, Chai H, Huang X, Yang W, Wang Q (2022) Activating cGAS-STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis. J Neuroinflammation 19:137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Duan N, Zhang Y, Tan S, Sun J, Ye M, Gao H, Pu K, Wu M, Wang Q, Zhai Q (2022) Therapeutic targeting of STING-TBK1-IRF3 signalling ameliorates chronic stress induced depression-like behaviours by modulating neuroinflammation and microglia phagocytosis. Neurobiol Dis 169:105739

    Article  CAS  PubMed  Google Scholar 

  91. Zhang D, Liu Y, Zhu Y, Zhang Q, Guan H, Liu S, Chen S, Mei C, Chen C, Liao Z, ** Y, Ouyang S, Feng XH, Liang T, Shen L, Xu P (2022) A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis. Nat Cell Biol 24:766–782

    Article  CAS  PubMed  Google Scholar 

  92. **e X, Wu X, Zhao D, Liu Y, Du Q, Li Y, Xu Y, Li Y, Qiu Y, Yang Y (2023) Fluvoxamine alleviates bleomycin-induced lung fibrosis via regulating the cGAS-STING pathway. Pharmacol Res 187:106577

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all the participants in the study.

Funding

This work was supported by Major Research Plan of National Natural Science Foundation of China (Grant No.92163213), General Program of National Natural Science Foundation of China (Grant No. 81970085), Tian** science and technology plan project (Grant No. 21JCZDJC00940), Tian** health science and technology projects (Grant No. TJWJ2022XK001), and Tian** Key Medical Discipline (Specialty) Construction Project (Grant No.TJYXZDXK-006 A).

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  1. Department of Geriatrics, Tian** Medical University General Hospital, Tian** Geriatrics Institute, Tian**, 300052, China

    Shuying Wang, ** Tan & Qiang Zhang

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  1. Shuying Wang
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  2. ** Tan
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  3. Qiang Zhang
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Contributions

The study was collaboratively conceived and designed by all authors. Material preparation, data collection and analysis were performed by Shuying Wang and ** Tan. The initial draft of the manuscript was composed by Shuying Wang, with subsequent revisions and inputs from all authors. The final manuscript has been read and approved by every author.

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Correspondence to Qiang Zhang.

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Ethics Approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Tian** Medical University Animal Care and Use Committee (IRB2022-DWFL-074, approval data: 02/21/2022).

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Wang, S., Tan, J. & Zhang, Q. Cytosolic Escape of Mitochondrial DNA Triggers cGAS-STING Pathway-Dependent Neuronal PANoptosis in Response to Intermittent Hypoxia. Neurochem Res 49, 2228–2248 (2024). https://doi.org/10.1007/s11064-024-04151-7

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