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

作者：Yina Zhu, Mei‐chen Wan, Yutong Fu, Junting Gu, Zhao-yang Ren, Yun Wang, Kehui Xu, Jing Li, Man‐Jiang Xie, Kai Jiao, Franklin Tay, Li‐na Niu · 发表于：International Journal of Oral Science · 年份：2025 · DOI：10.1038/s41368-025-00373-9 · 被引用次数：10 · 研究领域：Obstructive Sleep Apnea Research、High Altitude and Hypoxia、Neuroscience of respiration and sleep

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 N 6 -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.