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Mitochondrial Calcium Ion Nanogluttons Alleviate Periodontitis via Controlling mPTPs
Ping He1, Fengyi Liu2,3,4, Mingzheng Li2,3,4
1College of Stomatology, Chongqing Medical University, Chongqing, 401147, China.
Abstract:
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.
Insights
Novel nanogluttons target mitochondrial calcium overload to inhibit inflammatory macrophage activation and reduce bone loss in periodontitis. This approach offers a new strategy for treating chronic inflammatory diseases.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Immunology
Background:
- Mitochondrial permeability transition (mPT) pore opening is crucial in macrophage inflammatory responses.
- Mitochondrial calcium (mitoCa2+) overload triggers persistent mPT pore opening, creating a detrimental cycle with reactive oxygen species (ROS).
- Current treatments lack effective strategies to manage mitochondrial calcium overload and mPT pore dynamics.
Purpose of the Study:
- To investigate the role of persistent mPT pore opening in periodontitis initiation and macrophage activation.
- To develop a novel mitochondrial-targeted nanocarrier for calcium sequestration.
- To evaluate the therapeutic potential of these nanocarriers in periodontitis and associated bone loss.
Main Methods:
- Design and synthesis of mitochondrial-targeted nanogluttons (PEG-TPP conjugated PAMAM core-shell nanoparticles encapsulating BAPTA-AM).
- In vitro assessment of nanogluttons' ability to sequester mitochondrial calcium and inhibit macrophage inflammatory activation.
- In vivo evaluation of nanogluttons in a mouse model of periodontitis, assessing periodontal inflammation, osteoclast activity, and bone loss.
Main Results:
- Nanogluttons effectively sequestered mitochondrial calcium, preventing sustained mPT pore opening and inhibiting inflammatory macrophage activation.
- Mice treated with nanogluttons exhibited significantly reduced periodontal inflammation.
- Treatment led to diminished osteoclast activity and reduced bone loss in the periodontitis model.
Conclusions:
- Mitochondrial calcium overload and mPT pore opening are key drivers of periodontitis-induced inflammation and bone loss.
- Mitochondrial-targeted nanogluttons represent a promising therapeutic strategy for managing calcium overload in inflammatory diseases.
- This approach holds potential for treating periodontitis and other chronic inflammatory conditions linked to mitochondrial dysfunction.
