Key Takeaways & Executive Findings
- •• Mitophagy is a selective mitochondrial quality control mechanism that degrades damaged mitochondria via PINK1/Parkin and receptor-mediated pathways. • Excessive mitophagy in osteoclasts promotes bone resorption by maintaining ROS homeostasis, regulating energy metabolism, and enhancing osteoclast differentiation while inhibiting apoptosis. • Mitophagy exhibits dual roles in bone metabolism, acting as both a protective and detrimental factor depending on cellular context and extent. • Targeting mitophagy in osteoclasts represents a novel therapeutic strategy for osteoporosis, with potential for both Western and traditional Chinese medicine interventions.
Abstract
BACKGROUND: The development of osteoporosis is closely associated with the disruption of bone homeostasis, particularly due to the enhanced bone resorption activity of osteoclasts. Mitophagy, an autophagic pathway that selectively degrades damaged mitochondria, has recently been identified as being intricately linked to the pathogenesis and progression of osteoporosis. OBJECTIVE: To elucidate the mechanisms of mitophagy and its regulatory roles in osteoclasts and to investigate the potential mechanisms by which mitophagy influences bone homeostasis through the regulation of osteoclastogenesis and apoptosis. METHODS: The databases searched included PubMed, CNKI, WanFang Data, and VIP databases. The search terms were “mitophagy, bone metabolism, osteoclasts, bone homeostasis, bone resorption, bone loss” in Chinese and English. The search time frame was from January 2008 to April 2025. Based on the inclusion criteria, the search results were screened and excluded, and 101 articles were finally included for review and analysis. RESULTS AND CONCLUTION: Mitophagy is a crucial mitochondrial quality control mechanism within cells, primarily responsible for the selective elimination of damaged or dysfunctional mitochondria. The main pathways of mitophagy include the phosphatase and tensin homolog-induced kinase 1/E3 ubiquitin ligase pathway and the receptor-mediated mitophagy pathway. Mitophagy often exhibits dual beneficial and detrimental properties in the body. Excessive mitophagy can lead to imbalance of bone metabolism and subsequent osteoporosis by maintaining intracellular reactive oxygen species homeostasis, regulating energy metabolism, promoting osteoclast differentiation, inhibiting osteoclast apoptosis, and increasing bone resorption.
1. Introduction
Osteoporosis is a metabolic, systemic bone disease characterized by decreased bone density and strength, leading to increased bone fragility and fracture risk [1-3]. The pathogenesis of osteoporosis is closely related to the disruption of bone homeostasis, which is maintained by the balance between bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. When bone resorption exceeds bone formation, bone homeostasis is disrupted, leading to osteoporosis. Therefore, inhibiting osteoclast bone resorption is considered an important direction for the prevention and treatment of osteoporosis.
Mitochondria are recognized as the "energy factories" of cells, maintaining cellular energy metabolism through oxidative phosphorylation [4]. Mitophagy, as an important branch of autophagy, is a selective autophagic pathway that eliminates damaged or dysfunctional mitochondria and has unique mechanisms [5]. Studies have shown that mitochondrial dysfunction significantly affects cellular metabolism and can trigger the development and progression of many age-related bone diseases [6], suggesting a potential link between mitophagy and the occurrence of osteoporosis. This review aims to explore the potential mechanisms by which mitophagy regulates osteoclasts to prevent and treat osteoporosis, providing a theoretical basis for related research.
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Gao Jiabin, Li Tianqi, Xu Kun, Zhu Hanmin, Zhou Xi, Li Wei (2026). Mitophagy regulates osteoclasts: a new perspective for osteoporosis treatment. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21262
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Frequently Asked Questions
What is mitophagy and how does it relate to osteoporosis?
Mitophagy is a selective autophagic pathway that degrades damaged mitochondria, maintaining mitochondrial quality control. In osteoporosis, excessive mitophagy in osteoclasts can enhance bone resorption by promoting osteoclast differentiation and inhibiting apoptosis, leading to bone loss.
What are the main pathways of mitophagy?
The main pathways of mitophagy include the PINK1/Parkin-mediated pathway and receptor-mediated pathways (such as BNIP3/NIX and FUNDC1). These pathways selectively target damaged mitochondria for degradation.
How does mitophagy affect osteoclast function?
Mitophagy regulates osteoclast function by maintaining intracellular reactive oxygen species (ROS) homeostasis, modulating energy metabolism, promoting osteoclast differentiation, and inhibiting osteoclast apoptosis, thereby increasing bone resorption activity.
Can mitophagy be targeted for osteoporosis treatment?
Yes, targeting mitophagy in osteoclasts represents a novel therapeutic strategy. Both Western drugs and traditional Chinese medicine have been shown to modulate mitophagy in osteoclasts, offering potential avenues for osteoporosis prevention and treatment.
What is the dual role of mitophagy in bone metabolism?
Mitophagy has dual roles: it can be protective by clearing damaged mitochondria and preventing cellular dysfunction, but excessive mitophagy can lead to increased osteoclast activity and bone resorption, contributing to osteoporosis. The context and extent of mitophagy determine its net effect.
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