# Mechanisms and therapeutic potential of mitochondrial-targeted therapies in bone repair

## TL;DR

This review explores how targeting mitochondria can improve bone repair, offering a promising new strategy for treating difficult-to-heal bone defects.

## Contribution

The paper systematically reviews mitochondrial roles in bone repair and evaluates current mitochondrial-targeted therapeutic strategies.

## Key findings

- Mitochondrial dysfunction is a key factor in failed bone repair.
- Targeting mitochondria can enhance cellular energy metabolism and promote cell survival.
- Challenges include improving delivery efficiency and ensuring long-term safety.

## Abstract

Bone defect repair remains a significant challenge in orthopedics, particularly for critical-sized bone defects, which often result in nonunion. Traditional treatments have numerous limitations. Recent studies have highlighted the pivotal role of mitochondria as cellular energy and metabolic hubs influencing the function of osteoblasts, osteoclasts, and chondrocytes. Mitochondria regulate energy metabolism, ROS signaling, mitochondrial dynamics, and apoptosis, all of which are essential for maintaining proper bone function. Mitochondrial dysfunction has been identified as a key intrinsic factor contributing to the failure of bone repair. Thus, targeting mitochondria has emerged as a promising therapeutic strategy. This article systematically reviewed the various functional roles of mitochondria in bone repair and evaluated the current progress of mitochondrial-targeted therapeutic strategies. We focused on the mechanisms of action and preclinical advancements related to small molecule compounds, functionalized biomaterials, and advanced cell therapies, offering a theoretical foundation for their potential clinical application. Mitochondrial-targeted therapies show significant promise for enhancing bone repair by improving cellular energy metabolism, restoring redox homeostasis, optimizing mitochondrial quality control, and promoting cell survival. However, this field faces several challenges, including improving targeted delivery efficiency, ensuring long-term safety, and translating these strategies into clinical practice. Future research should prioritize the development of more precise delivery technologies, exploration of multi-target synergistic approaches, and rigorous clinical trials to support the practical application of mitochondrial-targeted therapies for clinical bone regeneration.

This review highlights the strong translational potential of mitochondrial-targeted therapies as a next-generation strategy for bone repair. By systematically linking specific mitochondrial dysfunctions to mechanism-based interventions. It provides a rational framework for developing treatments that enhance cellular fitness. Overcoming delivery and safety challenges through interdisciplinary efforts could revolutionize the management of critical-sized defects, particularly in compromised healing environments like aging or diabetes.