LPS-Induced Mitochondrial Damage via SLC41A1-Mediated Magnesium Ion Efflux Leads to the Pyroptosis of Dental Stem Cells.

IF 14.1 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yuan Liu, Chenyu Song, Liyuan Zhang, Xue Han, Chaoyuan Li, Yanhong Yan, Ludan Xing, Mengting Si, Bo Yang, Lingyuan Cheng, Akimi Muramatsu, Beizhan Jiang
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引用次数: 0

Abstract

Although regenerative endodontics demonstrate promise for dental pulp regeneration, chronic inflammation often hinders the success. This study aims to explore the mechanism whereby lipopolysaccharide (LPS) induces dental pulp regeneration failure. Transcriptomic profiling of LPS-stimulated dental pulp stem cells (DPSCs) reveals dysregulated cation homeostasis and increased magnesium (Mg2⁺) transmembrane transport. Mechanistically, LPS is observed to activate the transcription factor signal transducer and activator of transcription 5A (STAT5A), which binds to the solute carrier family 41 member 1 (SLC41A1) promoter, thereby upregulating the Mg2⁺ efflux transporter and depleting intracellular Mg2⁺ levels. Mg2⁺ efflux destabilizes the mitochondrial permeability transition pore (mPTP), thus facilitating its opening via the interaction of oligomycin sensitivity-conferring protein (OSCP) and cyclophilin D (CypD), which releases reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) and exacerbates oxidative stress. The released mtDNA activates the absent in melanoma 2 (AIM2) inflammasome, thereby amplifying gasdermin D (GSDMD)-mediated pyroptosis. Exogenous supplementation with Mg2⁺ restores intracellular Mg2⁺ homeostasis, suppresses mPTP opening, and reduces mtDNA and ROS leakage, thereby rescuing DPSCs viability and differentiation capacity. This study identifies SLC41A1-mediated Mg2⁺ dysregulation as a pivotal driver of LPS-induced mitochondrial damage and demonstrates that Mg2⁺ replenishment is a therapeutic strategy to counteract inflammation-driven regenerative failure.

slc41a1介导的镁离子外排诱导lps诱导的线粒体损伤导致牙干细胞热亡
虽然再生牙髓学显示出牙髓再生的希望,但慢性炎症常常阻碍成功。本研究旨在探讨脂多糖(LPS)诱导牙髓再生失败的机制。lps刺激的牙髓干细胞(DPSCs)的转录组学分析显示阳离子稳态失调和镁(Mg2 +)跨膜转运增加。从机制上看,LPS激活转录因子信号换能器和转录激活因子5A (STAT5A), STAT5A与溶质载体家族41成员1 (SLC41A1)启动子结合,从而上调Mg2 +外流转运体,消耗细胞内Mg2 +的水平。Mg2 +外溢破坏线粒体通透性过渡孔(mPTP)的稳定性,通过寡霉素敏感性赋予蛋白(OSCP)和亲环蛋白D (CypD)的相互作用促进其打开,释放活性氧(ROS)和线粒体DNA (mtDNA),加剧氧化应激。释放的mtDNA激活黑色素瘤2 (AIM2)炎性体中的缺失,从而放大气皮蛋白D (GSDMD)介导的焦亡。外源性补充Mg2 +恢复细胞内Mg2 +稳态,抑制mPTP开放,减少mtDNA和ROS泄漏,从而挽救DPSCs的活力和分化能力。该研究确定slc41a1介导的Mg2 +失调是lps诱导的线粒体损伤的关键驱动因素,并证明Mg2 +补充是一种对抗炎症驱动的再生衰竭的治疗策略。
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来源期刊
Advanced Science
Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
18.90
自引率
2.60%
发文量
1602
审稿时长
1.9 months
期刊介绍: Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.
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