An emerging role of mitochondrial quality control in bone metabolism: from molecular mechanisms to targeted therapeutic interventions

Abstract

The mitochondrial quality control system is the principal regulatory framework governing mitochondrial quantity, morphology, distribution, and functional integrity. This surveillance and regulatory machinery is essential for preserving cellular homeostasis and determining cellular differentiation. Mitochondria play a central role in maintaining the dynamic equilibrium between osteogenic differentiation and osteoclastic differentiation. Dysregulation of mitochondrial quality control can lead to disrupted mitochondrial homeostasis and functional impairments, disrupting the physiological processes of bone formation and bone resorption. However, comprehensive reviews elucidating the relationship between mitochondrial quality control and bone homeostasis are conspicuously lacking. This review systematically deconstructs the molecular architecture of mitochondrial quality control, elucidating the regulatory mechanism of each part (mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondrial redox) in bone-related cells. In addition, the mitochondrial quality control system in orchestrating cellular physiological activities is summarized to establish its indispensable in governing cellular homeostatic networks. Furthermore, the regulatory roles of the mitochondrial quality control system in bone-related cells and the balance between bone formation and resorption are reviewed. Finally, this review delineates the dysregulation of mitochondrial quality control in bone metabolic diseases and further advances mitochondrial quality control-targeted approaches for restoring mitochondria homeostasis, offering transformative strategies to treat bone metabolic diseases.

Keywords: Bone metabolism; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Oxidative stress.

Fig. 1

Mitochondrial quality control system regulates bone metabolism. Mitochondrial quality control is a pivotal regulatory mechanism essential for maintaining mitochondrial function and cellular homeostasis. It encompasses several interconnected processes, including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitochondrial redox balance. These processes operate synergistically to form an intricate regulatory network that ensures efficient cellular energy metabolism and homeostasis. Bone metabolism, a biological process heavily reliant on ATP, is profoundly influenced by mitochondrial quality control. Bone homeostasis is maintained under physiological conditions but is disrupted in pathological states. Dysregulation of MQC is closely implicated in the pathogenesis of various diseases. MQC dysfunction contributes to various bone metabolic diseases like osteoporosis, impaired fracture healing, osteoarthritis-related bone changes, and diabetes-associated bone loss. Under pathological conditions, when the functional activity of osteoblasts surpasses that of osteoclasts, bone formation predominates; conversely, enhanced osteoclast activity leads to increased bone resorption

Fig. 2

Overview of the mitochondrial quality control system. Mitochondrial quality control is essential for maintaining functional mitochondria and cellular health. Mitochondrial reactive oxygen species (mtROS) constitute a primary source of endogenous oxidative damage, targeting mitochondrial DNA (mtDNA), proteins, and lipids, thereby inducing mitochondrial dysfunction. To counteract this, mitochondrial fission facilitates the fission of damaged mitochondria into distinct fragments through asymmetric division, yielding both healthier daughter mitochondria and impaired mitochondria fragments. Mitochondrial fusion can then integrate mildly impaired fragments into the healthy network for potential repair. Conversely, severely damaged fragments are selectively targeted for degradation via mitophagy, preventing the accumulation of dysfunctional mitochondria and cytotoxic mtROS. To compensate for mitochondrial loss, mitochondrial biogenesis is activated, involving the synthesis, import, and assembly of new proteins and lipids, coupled with mtDNA replication, to regenerate functional mitochondria. A dynamic balance between fission and fusion is essential to meet cellular energy demands and maintain proper mitochondrial distribution. Failure in any MQC component compromises mitochondrial integrity, disrupts mitochondrial homeostasis, and ultimately contributes to cellular dysfunction

Fig. 3

Mitochondrial quality control and cellular function. MQC is intricately linked to cellular homeostasis and functional states through multifaceted regulatory mechanisms. MQC critically governs: oxidative phosphorylation for ATP production; mitochondrial genetic complementation; cell differentiation control; apoptosis regulation; and cell cycle progression control

Fig. 4

Effects of mitochondrial dynamics on bone metabolism. A) TMEM135 can augment the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) through the facilitation of DRP1-mediated mitochondrial fission, thereby attenuating osteoporosis in OVX mice. Reproduced with permission [171]. Copyright 2024, Elsevier. B) A new mitochondria-target orthopedic implant. The new orthopedic implant modulates mitochondrial dynamics to promote fusion for the enhancement of osteogenic differentiation. Reproduced with permission [156]. Copyright 2021, Wiley–VCH GmbH. C) DRP1 actively promotes osteoclast differentiation induced by RANKL. Reproduced with permission [166]. Copyright 2021, John Wiley & Sons. D) AMPKα1 is a negative regulator of osteoclast differentiation, which up-regulates MFN2, down-regulates DRP1 and down-regulates the number of mitochondria. Reproduced with permission [170]. Copyright 2023, Elsevier

Fig. 5

Effects of mitophagy on bone metabolism. A) l-arginine can promote angiogenesis and reduce bone loss by promoting PINK1/Parkin and Bnip3 mediated mitophagy to protect cells. Reproduced with permission [183]. Copyright 2024, Elsevier. B) WAC can activate mitophagy by protecting PINK1, promote MSC osteogenesis and enhance new bone formation in vitro and in vivo. Reproduced with permission [184]. Copyright 2025, Wiley–VCH GmbH. C) Guizhi Shaoyao Zhimu granules (GSZGs) facilitate PINK1/Parkin pathway-mediated mitophagy, thereby suppressing the generation of OCPs and mitigating bone erosion in rheumatoid arthritis (RA). Reproduced with permission [179]. Copyright 2023, Elsevier. D) PINK1 regulates mitochondrial homeostasis through mitophagy, thereby suppressing excessive osteoclast differentiation and bone resorption. Reproduced with permission [185]. Copyright 2024, Elsevier

Fig. 6

Effects of mitochondrial biogenesis on bone metabolism. A) Mitochondria-targeted polyphenol/amino acid assembled nanoparticles (EC NPs). EC NPs enhance osteogenic differentiation and bone regeneration by promoting AMPK-mediated mitochondrial biogenesis and regulating mitochondrial homeostasis, thereby increasing bone mass and bone mineral density. Reproduced with permission [195]. Copyright 2024, Wiley–VCH GmbH. B) A three-dimensional (3D) printed scaffold composed of polylactide (PLA) modified with europium (III)-organic ligands (polydopamine and chitooligosaccharide, PDA/COS@Eu). This scaffold stimulates bone repair by facilitating mitochondrial function and mitochondrial biogenesis. Reproduced with permission [196]. Copyright 2024, Elsevier. C) A 3D-printed molybdenum-containing scaffold. Mo ions inhibit osteoclast progenitor differentiation by inhibiting mitochondrial biogenesis, leading to enhanced bone regeneration. Reproduced with permission [197]. Copyright 2022, Springer Nature. D) Isobavachin (IBA) alleviates bone loss caused by periodontitis by inhibiting mitochondrial biogenesis and function to reduce osteoclast generation in vivo. Reproduced with permission [198]. Copyright 2024, Elsevier

Fig. 7

Effects of mitochondrial redox on bone metabolism. A) A mineralized zippered G4-Hemin DNAzyme hydrogel (MDH). MDH can significantly alleviate oxidative stress in osteoblasts, effectively restore mitochondrial membrane potential, and demonstrate excellent osteogenic activity. Reproduced with permission [207]. Copyright 2023, Wiley–VCH GmbH. B) Cinnamaldehyde (CIN) can effectively reduce the accumulation of mtROS, ameliorate mitochondrial dysfunction, and consequently restore the osteogenic differentiation potential of BMSCs, partially reversing ovariectomy (OVX)-induced bone loss. Reproduced with permission [208]. Copyright 2023, American Chemical Society. C) Tussilagone (TSG) inhibits the production of ATP and mtROS during OCs differentiation, thereby inhibiting OCs differentiation and bone resorption. Reproduced with permission [209]. Copyright 2023, Elsevier