Mitochondrial Calcium Ion Nanogluttons Alleviate Periodontitis via Controlling mPTPs

Abstract

The mitochondrial permeability transition (mPT) directly affects mitochondrial function in macrophages. Under inflammatory conditions, mitochondrial calcium ion (mitoCa 2+ ) overload triggers the persistent opening of mPT pores (mPTPs), further aggravating Ca 2+ 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 Ca 2+ . 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 mitoCa 2+ 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" Ca 2+ 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 mitoCa 2+ overload.

Mitochondrial Dysfunction in the Pathogenesis and Treatment of Oral Inflammatory Diseases

“…These changes were consistent with the alteration in TCA cycle genes and increased glycolytic gene expression [128]. He et al revealed that under inflammatory conditions, mitochondrial calcium overload in macrophages triggered the persistent opening of mitochondrial permeability transition pores, aggravating calcium overload and inducing mitochondrial dysfunction, forming an adverse cycle which contributed to the activation of periodontitis in vivo [129].…”

Synergistically remodulating H+/Ca2+ gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy

“…S26 † ). 47 Consequently, the significant mitochondrial depolarization by Ca@DNA–MF has been verified.…”

A Biomimetic Se‐nHA/PC Composite Microsphere with Synergistic Immunomodulatory and Osteogenic Ability to Activate Bone Regeneration in Periodontitis

“…Therefore, it is necessary to alleviate inflammation, create a homeostatic immune environment for inflammatory osteolytic diseases, and provide essential elements for regenerative tissue repair. [ 81 ] In conclusion, Se‐nHA/PC microspheres can effectively protect periodontal ligament attachments and alveolar bone from inflammatory tissue destruction and have a promising future for the treatment of periodontal tissues.…”