Platelet methyltransferase-like protein 4-mediated mitochondrial DNA metabolic disorder exacerbates oral mucosal immunopathology in hypoxia

Abstract

Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood. This condition compromises mucosal barrier integrity particularly in the gut and oral cavity. However, the mechanisms underlying this association remain unclear. This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions. Hypoxia upregulated methyltransferase-like protein 4 (METTL4) expression in platelets, resulting in N⁶-methyladenine modification of mitochondrial DNA (mtDNA). This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation, leading to cytosolic mtDNA accumulation. Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets. This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis. Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology. Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.

References

[1] HenigNR, PiersonDJ. Mechanisms of hypoxemia. Respir. Care Clin. N. Am., 2000, 6: 501-521

[2] LuftFC. Hypoxemia as a model for high altitude and cardiovascular risk reduction. J. Mol. Med., 2016, 94: 247-249

[3] TremblayJC, AinsliePN. Global and country-level estimates of human population at high altitude. Proc. Natl Acad. Sci. USA, 2021, 118: e2102463118

[4] BenjafieldAV, et al.. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir. Med, 2019, 7: 687-698

[5] BasnyatB, CumboTA, EdelmanR. Infections at high altitude. Clin. Infect. Dis., 2001, 33: 1887-1891

[6] JiaoJ, et al.. The prevalence and severity of periodontal disease in Mainland China: Data from the Fourth National Oral Health Survey (2015-2016). J. Clin. Periodontol., 2021, 48: 168-179

[7] SilvaLM, et al.. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science, 2021, 374: eabl5450

[8] KimTS, et al.. Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis. J. Exp. Med., 2023, 220: e20221751

[9] ZhangJ, et al.. Interactions of periodontal pathogens with platelets in the gingival crevicular fluid of patients with periodontitis. J. Clin. Periodontol., 2022, 49: 922-931

[10] WhitePC, et al.. Neutrophil extracellular traps in periodontitis: a web of intrigue. J. Dent. Res, 2016, 95: 26-34

[11] KoupenovaM, LivadaAC, MorrellCN. Platelet and megakaryocyte roles in innate and adaptive immunity. Circ. Res., 2022, 130: 288-308

[12] CaudrillierA, et al.. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest., 2012, 122: 2661-2671

[13] BrownL, YippBG. Inflammatory platelet death drives sepsis. Nat. Cardiovasc. Res., 2022, 1: 689-690

[14] SinghI, ChohanIS. Abnormalities of blood coagulation at high altitude. Int. J. Biometeorol., 1972, 16: 283-297

[15] GeX, et al.. Hypoxia-activated platelets stimulate proliferation and migration of pulmonary arterial smooth muscle cells by phosphatidylserine/LOX-1 signaling-impelled intercellular communication. Cell Signal, 2021, 87: 110149

[16] LehmannT, et al.. Platelet count and function at high altitude and in high-altitude pulmonary edema. J. Appl Physiol. (1985), 2006, 100: 690-694

[17] LiuF, et al.. Effects of altitude on human oral microbes. AMB Express, 2021, 11 41

[18] BianchiE, et al.. Relationship between periodontal disease and obstructive sleep apnea in adults: a systematic review. Dent. Res. J. (Isfahan), 2024, 21: 15

[19] MettrauxGR, GusbertiFA, GrafH. Oxygen tension (pO2) in untreated human periodontal pockets. J. Periodontol., 1984, 55: 516-521

[20] BryzekD, et al.. Triggering NETosis via protease-activated receptor (PAR)-2 signaling as a mechanism of hijacking neutrophils function for pathogen benefits. PLoS Pathog., 2019, 15: e1007773

[21] HirschfeldJ, et al.. Modulation of neutrophil extracellular trap and reactive oxygen species release by periodontal bacteria. Infect. Immun., 2017, 85: e00297-00217

[22] ChaoT, et al.. An inducible model for specific neutrophil depletion by diphtheria toxin in mice. Sci. China Life Sci., 2021, 64: 1227-1235

[23] NicoleM. Herman et al. Peripheral blood mononuclear cell gene expression in healthy adults rapidly transported to high altitude. Adv. Genomics Genet., 2015, 5: 1-9

[24] SalzmannM, et al.. Genetic platelet depletion is superior in platelet transfusion compared to current models. Haematologica, 2020, 105: 1738-1749

[25] YangM, et al.. STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion. Immunity, 2023, 56: 1013-1026.e1016

[26] AblasserA, ChenZJ. cGAS in action: Expanding roles in immunity and inflammation. Science, 2019, 363: eaat8657

[27] MachlusKR, ItalianoJE Jr.. The incredible journey: from megakaryocyte development to platelet formation. J. Cell Biol., 2013, 201: 785-796

[28] AnnarapuGK, et al.. Heme stimulates platelet mitochondrial oxidant production to induce targeted granule secretion. Redox Biol., 2021, 48: 102205

[29] SprengerHG, et al.. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity. Nat. Metab., 2021, 3: 636-650

[30] LiuH, et al.. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA. Nat. Cell Biol., 2024, 26: 878-891

[31] HaoZ, et al.. N(6)-Deoxyadenosine methylation in mammalian mitochondrial DNA. Mol. Cell, 2020, 78: 382-395.e388

[32] ReardonSD, MishaninaTV. Phosphorylation and acetylation of mitochondrial transcription factor A promote transcription processivity without compromising initiation or DNA compaction. J. Biol. Chem., 2022, 298: 101815

[33] KingGA, et al.. Acetylation and phosphorylation of human TFAM regulate TFAM-DNA interactions via contrasting mechanisms. Nucleic Acids Res., 2018, 46: 3633-3642

[34] ZhangF, et al.. Rectifying METTL4-mediated N(6)-methyladenine excess in mitochondrial dna alleviates heart failure. Circulation, 2024, 150: 1441-1458

[35] ChenY, MetzJE, GaoH, GaoX. Association between obstructive sleep apnea and periodontitis in Chinese male adults: a cross-sectional study. J. Prosthet. Dent., 2023, 130: 80-86

[36] AshourA. High altitude and its effects on oral health: a review of literature. J. Adv. Oral. Res., 2020, 11: 143-147

[37] XiaoX, et al.. Detection of bacterial diversity in rat’s periodontitis model under imitational altitude hypoxia environment. Arch. Oral. Biol., 2012, 57: 23-29

[38] HuangX, et al.. Targeting epigenetic crosstalk as a therapeutic strategy for EZH2-aberrant solid tumors. Cell, 2018, 175: 186-199.e119

[39] DutzanN, AbuslemeL, KonkelJE, MoutsopoulosNM. Isolation, characterization and functional examination of the gingival immune cell network. J. Vis. Exp., 2016, 1: 53736

[40] BrigidiGS, BamjiSX. Detection of protein palmitoylation in cultured hippocampal neurons by immunoprecipitation and acyl-biotin exchange (ABE). J. Vis. Exp., 2013, 18: 50031

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82325012)

the Shaanxi Key Scientific and Technological Innovation Team (2020TD-033)

National Youth Foundation of China(82301043)

Natural Science Basic Research Program of Shaanxi (Program No.2024JC-YBQN-0980)

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The Author(s)