2. Academic Validation
  3. Platelet methyltransferase-like protein 4-mediated mitochondrial DNA metabolic disorder exacerbates oral mucosal immunopathology in hypoxia

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

  • Int J Oral Sci. 2025 Jun 12;17(1):49. doi: 10.1038/s41368-025-00373-9.
Yina Zhu # 1,  Meichen Wan # 1,  Yutong Fu # 1,  Junting Gu 1,  Zhaoyang Ren 1,  Yun Wang 1,  Kehui Xu 1,  Jing Li 1,  Manjiang Xie 2,  Kai Jiao 3,  Franklin Tay 4,  Lina Niu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2 Department of Aerospace Physiology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 3 Department of Stomatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
  • 4 The Dental College of Georgia, Augusta University, Augusta, GA, USA.
  • 5 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China. niulina831013@126.com.
  • # Contributed equally.
PMID: 40506453 DOI: 10.1038/s41368-025-00373-9
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.

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