The pivotal role of mitochondria in osteoporosis: From pathogenesis to future therapies

Abstract

Osteoporosis, a prevalent metabolic bone disorder, exhibits an age-related increase in incidence, profoundly impacting patients’ quality of life. Recent studies have underscored the fundamental role of mitochondria in bone metabolism, emphasizing the intricate link mitochondrial dysfunction and the viability and functionality of bone cells. Beyond their role in energy production, mitochondria are critical in modulating cellular apoptosis, oxidative stress, and calcium ion homeostasis, all of which are essential for maintaining bone health. Emerging evidence suggests that mitochondrial dysfunction plays an integral role in the pathogenesis of osteoporosis, yet significant challenges persist in this field. This review seeks to elucidate the critical role of mitochondria in osteoporosis research, examine their intricate relationship with bone metabolism, and synthesize current research advances alongside future directions. Ultimately, it aims to offer novel insights for the prevention and treatment of osteoporosis.

Highlights

• •Basic Function and Structure of Mitochondria.
• •Biological Mechanisms of Osteoporosis.
• •Relationship between Mitochondria and Bone Metabolism.
• •Mitochondria Applications in Osteoporosis Research.

1. Introduction

Osteoporosis is a systemic skeletal disorder characterized by diminished bone mineral density and compromised bone microarchitecture, resulting in reduced bone strength and heightened fracture risk [1]. Recent research has underscored the critical role of mitochondria in bone metabolism [2]. Beyond serving as the primary source of cellular energy, mitochondria are integral to modulating key physiological processes, such as cell viability, apoptosis, and oxidative stress, all of which are essential for bone homeostasis [3]. Emerging evidence highlights mitochondrial dysfunction as a key contributor to osteoporosis pathogenesis, particularly in disrupting the delicate balance between bone formation and resorption [4]. Under physiological conditions, mitochondria sustain skeletal homeostasis by regulating osteoblast and osteoclast activities. In pathological states, however, mitochondrial dysfunction perturbs this equilibrium, thereby exacerbating osteoporosis development [5].

The dynamic properties and quality control mechanisms of mitochondria have garnered significant attention in the pathogenesis of osteoporosis [6]. Research indicates that mitochondrial fusion, fission, biogenesis, and mitophagy are critical for the viability and functionality of bone cells. Specifically, mitochondrial dynamics modulate the metabolic state and survival signaling of bone cells, thereby influencing bone metabolism homeostasis [7]. Consequently, mitochondria-targeted therapeutic strategies have emerged as promising interventions for osteoporosis-related conditions, particularly in managing diabetes-induced and postmenopausal osteoporosis [8].

Therefore, a deeper understanding of mitochondria's role in bone metabolism and its underlying mechanisms is crucial for elucidating the pathogenesis of osteoporosis and fostering the development of innovative therapeutic strategies. Mitochondrial-targeted interventions, including modulation of mitochondrial dynamics, enhancement of mitochondrial biogenesis, and optimization of mitochondrial function, offer promising avenues for future osteoporosis treatments [9]. This review elucidates the indispensable role of mitochondria in osteoporosis research, focusing on their intricate relationship with bone metabolism, synthesizing current research advances, and delineating future research directions to provide novel perspectives for the prevention and treatment of osteoporosis.

2. Basic Function and Structure of Mitochondria

Mitochondria, indispensable intracellular organelles, primarily drive energy production and metabolic regulation. They synthesize adenosine triphosphate (ATP) via oxidative phosphorylation to meet cellular energy demands and engage in diverse metabolic pathways, such as fatty acid oxidation and amino acid metabolism [10]. Additionally, mitochondria are pivotal in regulating cell signaling, proliferation, and apoptosis. Their intricate structure and multifaceted functions position them as a focal point in cellular physiology and pathology research.

2.1. Mitochondrial energy production and metabolism

Mitochondria are semi-autonomous organelles, their primary function is to generate most of the cell's adenosine triphosphate (ATP). This is achieved through aerobic cellular respiration, a highly efficient process that utilizes different fuel sources, such as glucose, fatty acids, and amino acids. These substrates are converted into acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle in the mitochondrial matrix [11].

The TCA cycle oxidizes acetyl-CoA in a series of reactions. These reactions produce high-energy electron carriers, mainly NADH and FADH2. These reduced coenzymes are crucial for the next stage of energy production: oxidative phosphorylation (OXPHOS). OXPHOS occurs across the inner mitochondrial membrane. During this process, electrons from NADH and FADH2 are transferred through protein complexes. The flow of electrons powers proton pumps that move protons into the intermembrane space. This creates a strong electrochemical gradient, known as the mitochondrial membrane potential (MMP). The return flow of protons through the ATP synthase complex drives the production of ATP [12].

This energy production is closely linked to cellular redox balance. The electron transport chain inevitably generates reactive oxygen species (ROS). Healthy mitochondria have strong antioxidant systems to neutralize ROS and maintain redox homeostasis. Cells also can adjust the balance between cytoplasmic glycolysis and mitochondrial OXPHOS, depending on developmental signals and environmental conditions. To maintain long-term efficiency, mitochondria undergo continuous quality control. Processes such as fusion, fission, and mitophagy work together to ensure the health and functionality of the mitochondrial network [13].

2.2. Mitochondrial quality control: dynamic homeostasis and renewal

Mitochondria possess their own genome (mtDNA), which encodes essential protein subunits for the ETC and ATP synthase, alongside the tRNAs and rRNAs required for their translation. However, the vast majority of the mitochondrial proteome (>99 %) is encoded by the nuclear genome, synthesized on cytoplasmic ribosomes, and subsequently imported into the organelle. This dual genetic origin necessitates a tightly coordinated regulation of protein synthesis to maintain cellular homeostasis [14]. Beyond the synthesis of individual proteins, the collective function of the mitochondrial proteome is critically dependent on the structural integrity and dynamic organization of the organelle itself. Mitochondria sustain their morphological and functional integrity through a continuous, dynamic equilibrium of fission and fusion. Dynamin-related protein 1 (Drp1) orchestrates mitochondrial fission, requiring recruitment to the mitochondrial membrane via receptors such as mitochondrial fission factor (Mff), mitochondrial fission 1 protein (Fis1), and mitochondrial dynamics protein (MiD49/51), where it oligomerizes and facilitates membrane scission through GTP hydrolysis [15]. Mitochondrial fusion is governed by outer membrane proteins Mfn1/2 and the inner membrane protein OPA1, which exists in two isoforms: long (L-OPA1), promoting fusion, and short (S-OPA1), inhibiting it. The equilibrium between L-OPA1 and S-OPA1 is essential for maintaining cristae structure and efficient energy metabolism. Disruption of this dynamic fission-fusion balance precipitates mitochondrial dysfunction [16]. When this equilibrium is disrupted, a crucial quality control process known as mitophagy-the selective autophagic degradation of damaged mitochondria-is activated to clear dysfunctional organelles [17]. On the other side of this quality control cycle is mitochondrial biogenesis, the process of generating new mitochondria [18].

2.3. From intracellular regulators to intercellular signaling hubs

Mitochondria, traditionally recognized for their role in energy production, have emerged as crucial signaling hubs that regulate cellular behavior within the bone microenvironment. At the cellular level, they influence survival and apoptosis by controlling the production of ROS and maintaining calcium balance [19]. Additionally, the morphology of mitochondria itself serves as a critical signal. Under conditions of significant stress, mitochondria undergo fragmentation, a hallmark of the cellular pause response that is essential for cell survival and recovery [20].

Notably, the signaling role of mitochondria extends beyond individual cells, introducing a new concept of intercellular communication. This process, known as intercellular mitochondrial transfer, enables mitochondria to act as mobile organelles that influence the fate of recipient cells. The transfer of mitochondria occurs through various mechanisms, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and direct cell-cell contact, with its impact on bone homeostasis being highly context-dependent [21].

3. Biological mechanisms of osteoporosis

Bone mineral density (BMD) quantifies the mineral content per unit volume of bone tissue, serving as a key indicator of bone strength and skeletal health. Osteoporosis, a metabolic bone disorders, is characterized by diminished BMD and compromised bone microarchitecture, resulting in heightened bone fragility and elevated fracture risk. Reduced BMD is intricately linked to multiple biological mechanisms, including bone cell dysfunction, disrupted bone metabolism homeostasis, and the interplay of genetic and environmental factors [22]. Research underscores that osteoporosis pathogenesis stems from an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption [23]. Thus, a comprehensive understanding of the biological mechanisms underlying the relationship between BMD and osteoporosis is of paramount importance for devising innovative therapeutic strategies.

Bone cells predominantly comprise osteoblasts, osteoclasts, and osteocytes. Osteoblasts drive bone formation by synthesizing the bone matrix and facilitating mineralization, while osteoclasts mediate bone resorption, contributing to skeletal homeostasis. Osteocytes, the most prevalent cell type in bone tissue, primarily govern mechanosensation and signal transduction within the bone. They modulate osteoblast and osteoclast activities through the secretion of cytokines and growth factors, thereby regulating bone metabolism and remodeling [24]. Emerging evidence underscores the master regulatory role of osteocytes in bone metabolism, with their dysfunction implicated in diminished BMD and osteoporosis pathogenesis [25].

3.1. Pathogenesis of osteoporosis

Osteoporosis pathogenesis is multifaceted, driven by an interplay of genetic, hormonal, nutritional, and inflammatory factors [26]. Aging, particularly post-menopause, exacerbates bone resorption and impedes bone formation due to declining estrogen levels, thereby accelerating osteoporosis development [27]. Long-term glucocorticoid (GC) use represents the primary cause of secondary osteoporosis. GCs enhance osteoclast differentiation and maturation by upregulating the RANKL/OPG ratio while concomitantly inducing apoptosis in osteoblasts and osteocytes, resulting in increased bone resorption, diminished bone formation, and disrupted bone homeostasis [28]. GCs further suppress insulin-like growth factor 1 (IGF-1), impairing type I collagen synthesis and accelerating bone matrix degradation [29]. Additionally, chronic low-grade inflammation represents a core mechanism in osteoporosis pathogenesis. Research demonstrates that inflammatory cytokines such as IL-1β and TNF-α, critically regulate bone metabolism by enhancing osteoclast differentiation and activity while suppressing osteoblast function [30].

3.2. Regulatory mechanism of bone metabolism

Bone metabolism is a dynamic equilibrium orchestrated by multiple signaling pathways, notably the Wnt/β-catenin and RANK/RANKL/OPG pathways [31]. The Wnt signaling pathway is a primary driver of osteoblast differentiation and function, while the RANK/RANKL/OPG pathway predominantly governs osteoclast formation and activity [32]. Furthermore, non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), critically regulate bone metabolism by modulating gene expression, thereby shaping bone cell functionality and metabolic homeostasis [25]. Emerging evidence suggests that targeting these signaling pathways offers promising therapeutic targets and strategies for osteoporosis management [33].

4. Relationship between Mitochondria and Bone Metabolism

Emerging evidence identifies mitochondrial dysfunction as a central pathological driver of osteoporosis. During aging, diminished mitochondrial bioenergetic capacity leads to metabolic dysregulation and heightened bone cell apoptosis, thereby exacerbating osteoporosis development [8].(Fig. 1).

Fig. 1.

Mechanisms of mitophagy in osteoporosis.

4.1. Mitochondria in osteoblasts

Osteoblasts, the primary effectors of bone formation, critically depend on mitochondrial homeostasis for optimal function. Mitochondria orchestrate osteoblast differentiation, mineralization, and viability through intricate mechanisms, including energy metabolism, calcium signaling, redox homeostasis, and autophagy [34]. During osteoblast differentiation, mitochondrial OXPHOS and the TCA cycle produce ATP, fueling bone matrix synthesis and mineralization [35]. The Wnt/β-catenin and BMP/Smad signaling pathways safeguard mitochondria function by upregulating mitochondrial gene expression and mitigating intracellular reactive oxygen species (ROS) levels [36,37]. Wnt signaling activation amplifies mitochondrial oxidative phosphorylation, thereby promoting osteogenic differentiation [38]. BMP signaling upregulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), enhancing mitochondrial metabolic activity and driving osteoblast differentiation [39]. Osteoblasts critically depend on optimal intracellular calcium levels to support bone matrix synthesis and mineralization [40]. Mitochondria modulate intracellular calcium homeostasis by sequestering Ca²⁺ via the mitochondrial calcium uniporter (MCU), preventing calcium overload and sustaining levels conducive to mineralization. Furthermore, mitochondria-associated membranes (MAMs) link the endoplasmic reticulum (ER) to mitochondria, facilitating calcium signaling and thereby orchestrating osteoblast functionality [41].

At physiological levels, ROS serve as signaling molecules that promote osteogenic differentiation [42]. In osteoporosis, however, mitochondrial dysfunction—manifesting as electron transport chain and loss of membrane potential—drives excessive ROS accumulation. This induces lipid peroxidation and ferroptosis, causing damage to DNA, proteins, and lipids, thereby suppressing osteoblast activity and inducing apoptosis [43,44]. Nrf2 activation upregulates mitochondrial antioxidant enzymes, mitigating ROS-mediated damage in osteoblasts [45]. Additionally, sirtuin proteins SIRT1 and SIRT3 sustain MMP through deacetylation, shielding osteoblasts from oxidative stress [46].

Mitophagy, a selective autophagic process, clears dysfunctional or damaged mitochondria, thereby sustaining energy metabolism homeostasis in osteoblasts and mitigating ROS accumulation [47]. In osteoblasts, mitophagy is predominantly orchestrated by the PINK1/Parkin pathway and the SIRT1 signaling axis [48]. Under physiological conditions, PINK1 is translocated to the mitochondrial matrix via its mitochondrial targeting sequence (MTS), where it is cleaved by MPP and PARL proteases and subsequently degraded, maintaining Parkin in an inactive state and suppressing mitophagy [49,50]. Upon mitochondria damage—such as loss of membrane potential or excessive ROS accumulation—PINK1 evades proteolytic degradation, accumulating on the translocase of the outer mitochondrial membrane (TOM), where it forms homodimers and undergoes autophosphorylation to initiate activation [51,52]. Activated PINK1 phosphorylates Parkin at Ser65 and ubiquitin molecules, relieving Parkin's autoinhibition [53]. Parkin subsequently exerts its E3 ubiquitin ligase activity, ubiquitinating outer mitochondrial membrane (OMM) proteins, including TOM20 and VDAC1 [[54], [55], [56]], thereby facilitating the recruitment of autophagy receptors such as p62/SQSTM1 and LC3 [57,58]. This orchestrates the clearance of damaged mitochondria through the autophagosome-lysosome pathway, mitigating ROS accumulation and apoptosis while promoting osteoblast viability and differentiation [59]. 17β-estradiol enhances osteoblast proliferation by activating PINK1/Parkin-mediated mitophagy via the GPR30-ERK1/2 signaling pathway [60]. Conversely, deficiencies in the PINK1/Parkin pathway precipitate mitochondrial dysfunction, downregulate osteogenic genes such as BMP2 and Collagen I, and impair bone formation capacity [60].

SIRT1 amplifies PGC-1α activity through deacetylation, thereby driving mitochondrial biogenesis, restoring mitochondrial function, and indirectly facilitating mitophagy [61]. Emerging evidence indicates that bone marrow-derived mesenchymal stem cells (BMSCs) differentiate into osteoblasts, promoting osteogenesis and angiogenesis, thus attenuating osteoporosis progression [62]. In MSCs, SIRT1 overexpression suppresses FOXO3a acetylation, enhances its nuclear translocation, and upregulates antioxidant genes, such as superoxide dismutase 2 (SOD2), mitigating mitochondrial ROS accumulation, preventing mitochondrial damage, and promoting autophagy [63]. SIRT1 knockout in MSCs impairs mitophagy, suppresses osteogenic differentiation, and downregulates bone formation markers, including BMP2 and Collagen I [63]. Recent studies demonstrate that the PI3K signaling pathway critically regulates mitophagy [64].

Ferroptosis, a recently identified form of cell death associated with iron metabolism, is implicated in osteoporosis due to dysregulated iron homeostasis [64]. In type 2 diabetes-associated osteoporosis (T2DOP), downregulation of mitochondrial ferritin (FtMt) activates excessive autophagy through the PINK1/Parkin pathway, thereby inducing ferroptosis in osteoblasts and suppressing bone formation [65]. These findings highlight a complex interplay between PINK1-mediated autophagy and ferroptosis, underscoring the need for further exploration of their underlying molecular mechanisms.

4.2. Mitochondria in osteoclasts

Mitochondria are also key determinants of bone resorption, particularly in orchestrating osteoclast function. As the principal effector cells of bone resorption, osteoclasts critically depend on mitochondrial OXPHOS to support differentiation and function. Receptor activator of nuclear factor κB ligand (RANKL) activates the ERK/p38 signaling pathways, upregulates the mitochondrial biogenesis gene PGC-1α, and enhances mitochondrial respiratory complex assembly and OXPHOS, thereby fulfilling the energy demands of pre-osteoclast fusion and differentiation [66,67]. RANKL-induced ROS bursts activate MAPK and NF-κB signaling pathways, driving nuclear translocation of NFATc1 and upregulating osteoclast differentiation markers, including TRAP and cathepsin K (CTSK) [68]. Mitochondrial OXPHOS not only provides the primary source of ATP but also generates substantial ROS via the ETC, fostering a microenvironment conducive to osteoclast differentiation [69]. However, excessive ROS accumulation precipitates MMP collapse, inducing apoptosis as a self-limiting mechanism [68]. Activation of the Nrf2/HO-1 pathway enhances the activity of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPX), mitigating excessive ROS and suppressing the NFATc1 signaling cascade, thereby inhibiting osteoclast differentiation [70]. Mitophagy, mediated by the PINK1/Parkin pathway, clears damaged mitochondria, stabilizes MMP, and mitigates ROS leakage, thereby suppressing NLRP3 inflammasome activation and alleviating inflammatory bone erosion [71]. However, excessive autophagy may disrupt OXPHOS by eliminating functional mitochondria, indirectly compromising osteoclast viability [72]. Ling [73] et al. demonstrated that SIRT3 enhances mitophagy by deacetylating and stabilizing PINK1, thus inhibiting osteoclast-mediated bone resorption. SIRT3 knockout or pharmacological inhibition diminishes mitophagy, leading to osteoclast overactivation and exacerbating bone loss in conditions such as estrogen deficiency or aging. Furthermore, mitophagy sustains energy supply for osteoclast differentiation by eliminating inefficient mitochondria. Nevertheless, current research on mitophagy in osteoclasts remains limited [74]. Elucidating the regulatory mechanisms of mitophagy in osteoclasts holds promise for novel therapeutic strategies targeting osteolytic diseases, including osteoporosis and osteoarthritis.

4.3. Mitochondrial dysfunctions and bone metabolism

Under physiological conditions, a homeostatic mechanism is maintained through the transfer of healthy mitochondria from osteolineage cells to myeloid cells, the precursors of bone-resorbing osteoclasts. Upon internalization, these exogenous mitochondria actively regulate the metabolic landscape of the recipient cell. Specifically, this process involves the inhibition of glutathione (GSH) metabolism, which ultimately induces ferroptosis [7]. This targeted induction of cell death effectively suppresses the differentiation of myeloid precursors into mature osteoclasts, thereby maintaining the crucial balance between bone formation and resorption. In pathological states such as osteoporosis, this homeostatic process is subverted [75]. Pro-inflammatory M1 macrophages become the primary donors, transferring damaged, ROS-producing mitochondria to MSCs. The reception of these dysfunctional organelles triggers a deleterious cascade within the MSCs, characterized by a burst of ROS and profound metabolic remodeling. This leads to the abnormal accumulation of succinate and subsequent activation of the hypoxia-inducible factor 1-alpha signaling pathway. Consequently, the osteogenic differentiation capacity of MSCs is severely impaired, contributing to the net bone loss that exacerbates the progression of osteoporosis [76].

Collectively, these findings reveal that intercellular mitochondrial transfer represents a sophisticated and bidirectional signaling mechanism integral to the regulation of bone metabolism. The directionality and functional outcome of this transfer are critically determined by the physiological or pathological state of the bone microenvironment (Fig. 2).

Fig. 2.

Mitochondrial dysfunction in bone metabolism.

4.4. Risk factors for mitochondria-mediated osteoporosis

Osteoporosis is intricately linked to mitochondrial dysfunction, with various risk factors disrupting mitochondrial metabolism, redox homeostasis, and quality control, thereby perturbing the dynamic equilibrium of bone formation and resorption [77]. Key risk factors include estrogen deficiency, diabetes, and obesity. Estrogen is pivotal in orchestrating mitochondrial biogenesis and oxidative stress modulation [78]. Through the estrogen receptor alpha (ERα) signaling pathway, estrogen upregulates PGC-1α, enhancing mitochondrial biogenesis and OXPHOS activity [79]. Postmenopausal estrogen decline impairs mitochondrial DNA (mtDNA) replication, diminishes ATP synthesis, and compromises osteoblast differentiation capacity [80]. Furthermore, estrogen deficiency suppresses antioxidant enzyme activity, such as SOD and CAT, exacerbates mitochondrial ROS accumulation, and triggers osteoblast ferroptosis via lipid peroxidation and MMP collapse [81]. Deletion of ERα amplifies RANKL-induced mitochondrial OXPHOS, driving osteoclast precursor differentiation and accelerating bone resorption [82]. Estrogen also suppresses osteoclast energy supply by inhibiting mitochondrial complex I activity [83]. In diabetic patients, particularly those with hyperglycemia and insulin resistance, mitochondrial function is profoundly impaired. Chronic hyperglycemia disrupts the ETC through FoxO1, diminishing OXPHOS efficiency and compromising ATP production [84]. Concurrently, a high-glucose environment impairs mitophagy, leading to the accumulation of dysfunctional mitochondria and exacerbating ROS bursts [85]. Disruption of insulin signaling pathway weakens mitochondrial β-oxidation by suppressing the PPAR pathway, resulting in lipotoxic metabolite accumulation. Defects in mitochondrial branched-chain amino acid transporters, such as SLC25A44, intensify systemic insulin resistance, perpetuating a metabolic vicious cycle [86,87]. During diabetes progression, increased mtDNA heterogeneity, such as mutations in the D-loop region, impairs ETC complex assembly and function [88]. Reduced mtDNA copy number emerges as a potential biomarker for diabetic osteoporosis [89]. Accumulation of lipid peroxidation products, such as MDA, induces osteoblast ferroptosis by inactivating glutathione peroxidase 4 (GPX4), with the protective role of mitochondrial ferritin (FTMT) diminished in a high-glucose environment [65]. A high-fat diet (HFD) disrupts mitochondria-associated endoplasmic reticulum membranes (MAMs), impairs calcium signaling, and reduces mitochondrial calcium uptake, leading to diminished pyruvate dehydrogenase (PDH) activity and TCA cycle dysfunction. Meanwhile, endoplasmic reticulum stress (ERS) activates the IRE1α/XBP1 pathway, upregulating fatty acid synthase expression, such as stearoyl-CoA desaturase 1 (SCD1), thereby accelerating lipid accumulation [90,91]. A high-fat diet (HFD) drives BMSCs differentiation toward adipocytes by suppressing the Wnt/β-catenin pathway, notably through upregulation of Dickkopf-1 (DKK1), and activating peroxisome proliferator-activated receptor gamma (PPARγ). Mitochondrial ROS accumulation inhibits Runx2 and Osterix expression via NF-κB-mediated inflammatory signaling, compromising osteogenic potential [92,93]. Excessive fatty acid metabolism in bone tissue results in acetyl-CoA accumulation, which suppresses antioxidant gene expression, such as GPX4, through histone acetylation. Concurrently, mitochondrial lipid peroxidation, catalyzed by acyl-CoA synthetase long-chain family member 4 (ACSL4), induces osteoblast ferroptosis, while HFD restricts glucose uptake, diminishes ATP production, and impairs bone matrix mineralization [94,95].

5. Mitochondria applications in osteoporosis research

Targeting osteocytic mitochondrial dysfunction has rapidly moved from mechanistic exploration to translational application in OP research. Recent breakthroughs focus on three main areas: molecular-specific quality control pathways, novel death modalities, and advanced delivery systems.

5.1. Modulating mitochondrial quality control and dynamics

A primary strategy is to restore the homeostatic balance of the mitochondrial network by targeting mitochondrial quality control (MQC) machinery. This involves enhancing the selective removal of damaged organelles (mitophagy), regulating mitochondrial network architecture (dynamics), and promoting the synthesis of new, functional mitochondria (biogenesis) [6].

Defective mitophagy leads to the accumulation of dysfunctional, ROS-generating mitochondria, a hallmark of cellular senescence and a driver of osteoporotic bone loss. Activating this clearance pathway is a key therapeutic goal. The canonical PINK1/Parkin pathway has been validated as a critical target. Its activation has been shown to protect osteoblasts from apoptosis induced by oxidative stressors like Advanced Oxidation Protein Products (AOPPs) [96]. Furthermore, novel regulators of this pathway are being discovered. For instance, the activation of large-conductance Ca²⁺-activated K⁺ (BK) channels prevents diabetes-induced osteopenia by modulating mitochondrial Ca²⁺ levels, which in turn fine-tunes a specific mitophagy axis involving the inner membrane carrier SLC25A5/ANT2 and the core PINK1-PRKN machinery [97]. Sirtuins, particularly SIRT1 and SIRT3, also play a crucial role by deacetylating key mitophagy components, and compounds like resveratrol that upregulate SIRT1 have shown promise in enhancing mitophagy and improving bone parameters in osteoporotic models [98].

The architectural integrity of the mitochondrial network, maintained by a balance of fission and fusion, is essential for its function. In osteoporotic conditions, this balance often shifts towards excessive fission and fragmentation [99]. The small molecule Mdivi-1, an inhibitor of the primary fission protein Drp1, represents a potential therapeutic by preventing mitochondrial fragmentation and subsequent dysfunction [100]. Beyond dynamics, the physical and functional interface between mitochondria and the endoplasmic reticulum—the mitochondria-associated ER membranes (MAMs)—has emerged as a novel therapeutic node [101]. The Sigma-1 receptor (Sigmar1), a chaperone enriched at the MAM, has been identified as a negative regulator of osteoclastogenesis. Mechanistically, Sigmar1 activation promotes the ER-associated degradation (ERAD) of the Ca²⁺ pump SERCA2, thereby altering intracellular Ca²⁺ oscillations crucial for osteoclast differentiation.This highlights targeting protein stability at the MAM as a novel anti-resorptive strategy [102].

To complement the clearance of damaged mitochondria, promoting the synthesis of new, healthy organelles is equally important. The natural isoflavone Genistein has been shown to mitigate the senescence of BMSCs from ovariectomized rats. It achieves this by activating Estrogen-related receptor α (ERRα), a nuclear receptor that serves as a master regulator of mitochondrial biogenesis and also primes the cells for mitophagy [103]. This demonstrates that restoring the entire mitochondrial turnover cycle—biogenesis coupled with degradation—offers a potent strategy to combat age-related and estrogen-deficiency-induced OP.

5.2. Targeting mitochondrial-driven programmed cell death pathways

Recent research has expanded the focus from classical apoptosis to other forms of regulated cell death that are intrinsically linked to mitochondrial dysfunction, including ferroptosis and pyroptosis [104].

The natural product Poliumoside has been demonstrated to ferroptosis against T2DOP by suppressing this process. Its protective effect is mediated through the activation of the Nrf2/GPX4 signaling axis, a central pathway that detoxifies lipid peroxides and maintains mitochondrial redox homeostasis [105]. This identifies the direct inhibition of mitochondrial lipid peroxidation as a viable therapeutic approach.

Pyroptosis is an inflammatory form of cell death executed by gasdermin proteins, which can be triggered downstream of mitochondrial stress. In postmenopausal osteoporosis (PMOP), osteoblast pyroptosis contributes to the net loss of bone-forming cells [106]. The flavonoid Luteolin has been shown to rescue PMOP in preclinical models by alleviating osteoblast pyroptosis. This protective effect is achieved through the activation of the pro-survival PI3K-AKT signaling pathway, which stabilizes mitochondrial function and prevents the downstream activation of the pyroptotic cascade [107]. This suggests that preserving the osteoblast pool by targeting pyroptosis is a promising strategy.

5.3. Advanced therapeutic modalities and delivery systems

Overcoming challenges related to drug specificity, bioavailability, and systemic efficacy has led to the development of sophisticated therapeutic platforms that target mitochondria with greater precision.

A highly innovative approach utilizes multifunctional nanoparticles designed for a dual therapeutic impact. For example, nanoparticles composed of mesoporous silica loaded with 4-octyl itaconate and coated with a cerium-tannic acid network (MSN-OI@Ce-TA) have been engineered. These nanoparticles synergistically treat osteoporosis by simultaneously reprogramming the mitochondrial respiratory chain complex in inflammatory macrophages and inducing favorable epigenetic modifications (e.g., histone acetylation/methylation). This represents a paradigm shift towards integrated therapies that target both metabolic and gene-regulatory networks governed by mitochondria [108].

Cell-free strategies offer a means to deliver functional mitochondrial components systemically. Mitochondrial transplantation, the isolation and delivery of healthy mitochondria to damaged tissues, is an emerging field with preclinical promise. A more nuanced approach involves the use of Embryonic Stem Cell-derived Apoptotic Vesicles (ESC-apoVs). These vesicles can ameliorate bone aging phenotypes by transferring their cargo to aged BMSCs. Mechanistically, ESC-apoVs deliver the protein TCOF1, which upregulates mitochondrial protein transcription and promotes FLVCR1-mediated mitochondrial functional homeostasis [109]. This approach leverages the regenerative cargo of apoptotic bodies as a novel, cell-free method for systemic mitochondrial rejuvenation in the aging skeleton.

5.4. Mitochondrial biomarkers for diagnosis and prognosis

The complexity of mitochondrial involvement in OP necessitates a systems biology approach to identify reliable biomarkers. By integrating public datasets (e.g., from the Gene Expression Omnibus, GEO) with advanced computational methods like Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms, researchers have successfully identified key hub genes and biomarkers. These analyses have pinpointed genes related to mitochondrial dysfunction and co-regulated pathways like ER stress (e.g., AAAS, ESR1, SLC12A2, TAF15, VAMP2) [110] and those at the intersection of programmed cell death and mitochondrial function (e.g., DAP3, BIK, ACAA2) [111]. These candidate biomarkers, once clinically validated, could offer powerful new tools for the early diagnosis, risk stratification, and prognostic assessment of osteoporosis.

5.5. Natural compounds and small molecules targeting mitochondria

A growing armamentarium of natural compounds and small molecules is being investigated for their mitochondria-modulating properties in OP. Myrislignan, which inhibits osteoclastogenesis by suppressing mitochondrial function and downstream ERK signaling [112]. The natural compound resveratrol enhances mitophagy in osteoblasts by upregulating SIRT1 expression and activating the PI3K/Akt/mTOR signaling pathway, significantly improving bone mineral density (BMD) while reducing serum alkaline phosphatase and osteocalcin levels in osteoporotic rat models [64]. Leonurine, which activates mitophagy via the PI3K/Akt/mTOR pathway to protect BMSCs from oxidative stress [113]. Dimemorfan, an agonist of the MAM-resident Sigmar 1, which inhibits osteoclastogenesis. These compounds provide a rich source of lead structures for developing novel, mitochondria-targeted pharmacotherapies for osteoporosis [102].

6. Future research directions and challenges

6.1. Novel mitochondrial targeting drugs

Drugs targeting osteocytic mitochondria have opened up a promising frontier for the development of novel OP treatments. The journey from fundamental discovery to clinical application, however, is fraught with challenges that demand rigorous and targeted future research. Key areas of focus will need to include a deeper mechanistic elucidation of mitochondrial crosstalk, the translation of promising preclinical compounds, the development of sophisticated therapeutic platforms, and the establishment of biomarkers for personalized medicine.

A critical avenue for future investigation involves deciphering the intricate crosstalk between different MQC pathways. While studies have independently highlighted the therapeutic potential of modulating mitophagy, mitochondrial dynamics, or biogenesis, these processes are deeply interconnected. For instance, the therapeutic efficacy of a mitophagy-inducing agent may depend on a functioning mitochondrial fission machinery to first segregate the damaged organelles [114]. Future studies, likely in advanced preclinical animal models, must therefore explore these pathways in concert. A key challenge will be to determine how targeting one MQC component affects the others and the overall homeostatic balance. While Mdivi-1 has shown efficacy in preventing bone loss in animal studies, its clinical translation is hampered by concerns regarding off-target effects, including inhibition of mitochondrial Complex I [115]. Developing more specific modulators and understanding the integrated MQC response will be crucial for safe and effective intervention.

Another nascent but highly significant area is the modulation of intercellular mitochondrial transfer. The discovery that this process regulates the fate of both osteoclast and osteoblast precursors is a paradigm shift. However, our understanding is still in its infancy. Future research must identify the precise molecular signals that trigger and direct this transfer. The clinical application is limited by our current inability to safely and specifically control this process in vivo. Thus, before this concept can be therapeutically exploited, the fundamental signaling language governing mitochondrial exchange must be decoded.

Translating the therapeutic potential of natural compounds and small molecules identified in preclinical studies represents a major challenge centered on pharmacology and drug delivery. Compounds like Poliumoside and Luteolin have demonstrated remarkable efficacy in specific animal models of OP [105,107]. The primary limitation for their clinical use is their often-poor bioavailability, rapid metabolism, and the difficulty in achieving sustained therapeutic concentrations at the target site (bone). Future efforts must focus on advanced formulation and drug delivery strategies. This leads to the development of sophisticated therapeutic platforms. While these platforms have shown great promise in animal models, their path to the clinic is long and challenging, requiring extensive studies on long-term biocompatibility, biodistribution, clearance, and scalability of manufacturing.

Perhaps the most innovative and most challenging direction is the development of cell-free regenerative therapies. Extracellular vesicles avoid many safety issues associated with live cell therapy [116]. However, clinical application faces huge obstacles. This includes the standardization and large-scale manufacturing of therapeutic vesicles, the complete characterization of their complex molecular cargo, as well as the understanding of their in vivo stability, targeting, and dose-response relationship. Conducting long-term safety and efficacy studies in large animal models is a necessary prerequisite before considering clinical trials.

6.2. Mitochondria mediate of individual variability in osteoporosis

Individual variability significantly influences the onset and progression of osteoporosis, with mitochondria, as central regulators of cellular energy metabolism and signal transduction, emerging as pivotal mediators. Mitochondrial function and dynamics exhibit substantial inter-individual variation, driven by factors such as genetics, age, sex, and lifestyle [27]. In susceptible individuals, mitochondrial dysfunction disrupts the balance between bone formation and resorption, thereby exacerbating osteoporosis development. Moreover, interactions between mitochondria and signaling pathways, notably the p38 MAPK pathway, critically modulate bone metabolism [117]. Future research should elucidate how mitochondrial function underpins individual differences in osteoporosis to facilitate the development of personalized therapeutic strategies.

6.3. Mitochondrial interactions with other biological pathways

Mitochondria, beyond their role in energy metabolism, engage in intricate crosstalk with diverse biological pathways, critically influencing osteoporosis pathogenesis. Interactions between mitochondria and the endoplasmic reticulum (ER) are pivotal for maintaining calcium homeostasis and orchestrating cellular signal transduction, thereby modulating bone cell function and viability [118]. Additionally, mitochondria regulate oxidative stress and inflammatory responses, both intricately linked to osteoporosis development [119]. Future research should prioritize elucidating the specific mechanisms governing mitochondrial interactions with other cellular signaling pathways to uncover novel therapeutic targets for osteoporosis. Integrating insights into mitochondrial function with its interplay across biological pathways holds promise for pioneering innovative research and treatment strategies.

7. Conclusion

Mitochondria, as the primary energy generators within cells, have emerged as critical regulators in osteoporosis, drawing increasing research focus. Comprehensive analysis of contemporary studies underscores that mitochondrial function is indispensable for bone metabolism and intricately linked to the pathogenesis and progression of osteoporosis. This insight offers a novel perspective, emphasizing the importance of prioritizing mitochondrial health in elucidating the mechanisms underlying osteoporosis.

Mounting evidence underscores the multifaceted roles of mitochondria in orchestrating bone cell function, preserving skeletal integrity, and attenuating oxidative stress. Nevertheless, inconsistencies across studies, driven by variations in experimental design, model systems, and methodological approaches, highlights the urgent need for interdisciplinary collaboration. Integrating insights from molecular biology, cell biology, and clinical medicine is essential to developing a systematic and comprehensive framework for understanding mitochondrial contributions to bone diseases.

To propel mitochondrial research in osteoporosis, future studies should prioritize elucidating the specific mechanisms through which mitochondrial dysfunction disrupts bone cell metabolism and induces apoptosis. Furthermore, the utility of mitochondrial biomarkers for early diagnosis and prognosis assessment warrants rigorous evaluation. Lastly, the development of mitochondria-targeted therapeutic strategies, including enhancing mitochondrial biogenesis and restoring mitochondrial function, holds promise for pioneering innovative approaches to the prevention and treatment of osteoporosis.

In conclusion, mitochondria play a pivotal role in osteoporosis research, underscoring their profound biological significance. Sustained exploration of their contributions holds substantial promise for the developing innovative interventions to enhance bone health and mitigate the risk of osteoporotic fractures.

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Funding

Scientific Research Project of Jiangsu Provincial Health Commission (LKM2024057, H2023072), and Development Fund of The Affiliated Hospital of Xuzhou Medical University (XYFM202451), Scientific Research Project of Suqian Municipal Health Commission (ZD202406).

CRediT authorship contribution statement

Ce Shi: Conceptualization, Funding acquisition, Software, Supervision, Writing – original draft, Writing – review & editing. Lei Chen: Investigation, Software, Supervision, Writing – original draft, Writing – review & editing. Jinshuang Li: Formal analysis, Resources, Software. Tingting Shi: Methodology, Software. Chun Yang: Conceptualization, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Liguo Zhao: Conceptualization, Software, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.