线粒体钙离子纳米贪食通过控制 mPTP 缓解牙周炎,Advanced Healthcare Materials

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线粒体钙离子纳米贪食通过控制 mPTP 缓解牙周炎
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-03-12 , DOI: 10.1002/adhm.202203106
Ping He ₁ , Fengyi Liu _{2,

3,

4} , Mingzheng Li _{2,

3,

4} , Mingxing Ren ₁ , Xu Wang ₁ , Yangjia Deng ₁ , Xianghao Wu ₁ , Yuzhou Li _{2,

3,

4} , Sheng Yang _{2,

3,

4} , Jinlin Song _{2,

3,

4}

Affiliation

线粒体通透性转变（mPT）直接影响巨噬细胞中的线粒体功能。炎症条件下，线粒体钙离子（mitoCa ²⁺）过载触发mPT孔（mPTPs）持续打开，进一步加剧Ca ²⁺过载并增加活性氧（ROS），形成恶性循环。然而，目前还没有针对mPTPs的有效药物来限制或卸载过量的Ca ²⁺。新发现牙周炎的发生和促炎巨噬细胞的激活依赖于mPTPs的持续过度开放，而mPTPs主要由mitoCa ^2+触发过载并促进线粒体 ROS 进一步渗漏到细胞质中。为了解决上述问题，设计了靶向线粒体的“纳米贪食者”，其表面缀合有 PEG-TPP，PAMAM 表面缀合，而 BAPTA-AM 封装在核心内。这些纳米贪食者可以有效地“吞噬”Ca ²⁺线粒体周围和内部有效控制 mPTP 的持续开放。结果，纳米贪食者显着抑制巨噬细胞的炎症激活。进一步的研究还出乎意料地揭示，小鼠局部牙周炎症的减轻伴随着破骨细胞活性的减弱和骨质流失的减少。这为线粒体靶向干预牙周炎炎症性骨质流失提供了一种有前途的策略，并且可以扩展到治疗与 mitoCa ²⁺过载相关的其他慢性炎症性疾病。

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Mitochondrial Calcium Ion Nanogluttons Alleviate Periodontitis via Controlling mPTPs

The mitochondrial permeability transition (mPT) directly affects mitochondrial function in macrophages. Under inflammatory conditions, mitochondrial calcium ion (mitoCa²⁺) overload triggers the persistent opening of mPT pores (mPTPs), further aggravating Ca²⁺ overload and increasing reactive oxygen species (ROS) to form an adverse cycle. However, there are currently no effective drugs targeting mPTPs to confine or unload excess Ca²⁺. It is novelly demonstrated that the initiation of periodontitis and the activation of proinflammatory macrophages depend on the persistent overopening of mPTPs, which is mainly triggered by mitoCa²⁺ overload and facilitates further mitochondrial ROS leakage into the cytoplasm. To solve the above problems, mitochondrial-targeted “nanogluttons” with PEG-TPP conjugated to the surface of PAMAM and BAPTA-AM encapsulated in the core are designed. These nanogluttons can efficiently “glut” Ca²⁺ around and inside mitochondria to effectively control the sustained opening of mPTPs. As a result, the nanogluttons significantly inhibit the inflammatory activation of macrophages. Further studies also unexpectedly reveal that the alleviation of local periodontal inflammation in mice is accompanied by diminished osteoclast activity and reduced bone loss. This provides a promising strategy for mitochondria-targeted intervention in inflammatory bone loss in periodontitis and can be extended to treat other chronic inflammatory diseases associated with mitoCa²⁺ overload.

更新日期：2023-03-12

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