Mitochondrial quality control as a unifying regulatory platform in inflammatory bone diseases
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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Mitochondrial quality control (MQC) maintains healthy mitochondria in bone and joint cells.
MQC failure amplifies oxidative stress and inflammation, driving bone loss and cartilage damage.
MQC-targeted therapies may restore mitochondrial function and support bone tissue repair.
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ABSTRACT
Inflammatory bone diseases, including periodontitis, osteoporosis, and osteoarthritis, are traditionally investigated as distinct pathological entities, despite sharing common features of chronic inflammation and impaired tissue regeneration. A unifying regulatory framework that mechanistically links these conditions, however, remains largely undefined. Here, we propose mitochondrial quality control (MQC) as a unifying regulatory platform that integrates inflammatory signaling, cellular metabolic fitness, and fate determination within bone and joint microenvironments. MQC comprises coordinated processes that maintain mitochondrial homeostasis, including mitochondrial dynamics, mitophagy, biogenesis, and emerging mechanisms such as mitochondrial-derived vesicles, mitocytosis, mitochondrial unfolded protein response, and mitochondrial transfer. Disruption of these pathways amplifies oxidative stress and inflammatory cascades, promoting cellular senescence and apoptosis, thereby exacerbating bone loss and cartilage degradation. This review highlights MQC dysfunction as a shared pathological axis across inflammatory bone diseases rather than a disease-specific consequence. Importantly, we frame MQC as a programmable therapeutic platform and propose a stratified intervention paradigm, in which stage-dependent modulation of mitochondrial quality, ranging from pharmacological regulation to nanotechnology-enabled mitochondrial repair and mitochondrial transfer, may enable precision treatment. This framework positions MQC at the interface of inflammation, metabolism, and regeneration, offering a multidisciplinary perspective for the development of next-generation therapies for inflammatory bone diseases. -
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REFERENCES
[1] Gou H., Wang T., Chen Y., et al. (2025). Role of Pink1 in regulating osteoclast differentiation during periodontitis. J. Dent. Res. 104:753−762. DOI:10.1177/00220345251315723 [2] Li Z., Liang S., Ke L., et al. (2024). Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics. Pharmacol. Res. 208:107383. DOI:10.1016/j.phrs.2024.107383 [3] Sanchez-Lopez E., Coras R., Torres A., et al. (2022). Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol. 18:258−275. DOI:10.1038/s41584-022-00749-9 [4] Shen K., Zhou H., Zuo Q., et al. (2024). GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression. Nat. Commun. 15:10923. DOI:10.1038/s41467-024-55335-2 [5] Sczepanik F.S.C., Grossi M.L., Casati M., et al. (2020). Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol. 2000 84:45–68. DOI:10.1111/prd.12342 [6] Yu B. and Wang C.Y. (2022). Osteoporosis and periodontal diseases – an update on their association and mechanistic links. Periodontol. 2000 89:99–113. DOI:10.1111/prd.12422 [7] Ansari M.Y., Ahmad N. and Haqqi T.M. (2020). Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols. Biomed. Pharmacother. 129:110452. DOI:10.1016/j.biopha.2020.110452 [8] Komatsu N. and Takayanagi H. (2022). Mechanisms of joint destruction in rheumatoid arthritis — immune cell–fibroblast–bone interactions. Nat. Rev. Rheumatol. 18:415−429. DOI:10.1038/s41584-022-00793-5 [9] Hofstee M.I., Muthukrishnan G., Atkins G.J., et al. (2020). Current concepts of osteomyelitis: From pathologic mechanisms to advanced research methods. Am. J. Pathol. 190:1151−1163. DOI:10.1016/j.ajpath.2020.02.007 [10] Yao F., Bao Y., Meng Q., et al. (2025). Periprosthetic osteolysis: Mechanisms and potential treatment strategies. Cell. Signal. 131:111758. DOI:10.1016/j.cellsig.2025.111758 [11] Zhang Q., Wei J., Liu Z., et al. (2022). STING signaling sensing of DRP1-dependent mtDNA release in Kupffer cells contributes to lipopolysaccharide-induced liver injury in mice. Redox Biol. 54:102367. DOI:10.1016/j.redox.2022.102367 [12] Newman L.E. and Shadel G.S. (2023). Mitochondrial DNA release in innate immune signaling. Annu. Rev. Biochem. 92:299−332. DOI:10.1146/annurev-biochem-032620-104401 [13] Hong W.L., Huang H., Zeng X., et al. (2024). Targeting mitochondrial quality control: New therapeutic strategies for major diseases. Mil. Med. Res. 11:59. DOI:10.1186/s40779-024-00556-1 [14] Zhu H., Tan Y., Du W., et al. (2021). Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control. Redox Biol. 38:101777. DOI:10.1016/j.redox.2020.101777 [15] Li B., Liu F., Chen X., et al. (2024). FARS2 deficiency causes cardiomyopathy by disrupting mitochondrial homeostasis and the mitochondrial quality control system. Circulation 149:1268−1284. DOI:10.1161/circulationaha.123.064489 [16] Roca-Portoles A. and Tait S.W.G. (2021). Mitochondrial quality control: From molecule to organelle. Cell. Mol. Life Sci. 78:3853−3866. DOI:10.1007/s00018-021-03775-0 [17] Liu B.H., Xu C.Z., Liu Y., et al. (2024). Mitochondrial quality control in human health and disease. Mil. Med. Res. 11:32. DOI:10.1186/s40779-024-00536-5 [18] Monzel A.S., Enríquez J.A. and Picard M. (2023). Multifaceted mitochondria: Moving mitochondrial science beyond function and dysfunction. Nat. Metab. 5:546−562. DOI:10.1038/s42255-023-00783-1 [19] Flores-Romero H., Dadsena S. and García-Sáez A.J. (2023). Mitochondrial pores at the crossroad between cell death and inflammatory signaling. Mol. Cell 83:843−856. DOI:10.1016/j.molcel.2023.02.021 [20] Li W., Gui Y., Guo C., et al. (2025). Molecular mechanisms of mitochondrial quality control. Transl. Neurodegener. 14:45. DOI:10.1186/s40035-025-00505-5 [21] Ghifari A.S., Vazquez-Calvo C., Carlström A., et al. (2025). Interconnectivity of mitochondrial protein biogenesis and quality control. Trends Biochem. Sci. 50:1102−1117. DOI:10.1016/j.tibs.2025.09.004 [22] Kim S., Choi C., Son Y., et al. (2025). BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation. Autophagy 21:2009−2027. DOI:10.1080/15548627.2025.2487035 [23] Guo Q.Q., Wang S.S., Jiang X.Y., et al. (2025). Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 122:e2502841122. DOI:10.1073/pnas.2502841122 [24] Rabinovich-Nikitin I., Rasouli M., Reitz C.J., et al. (2021). Mitochondrial autophagy and cell survival is regulated by the circadian clock gene in cardiac myocytes during ischemic stress. Autophagy 17:3794−3812. DOI:10.1080/15548627.2021.1938913 [25] Pokharel M.D., Garcia-Flores A., Marciano D., et al. (2024). Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics. Redox Biol. 70:103049. DOI:10.1016/j.redox.2024.103049 [26] Tang X., Zhong L., Tian X., et al. (2023). RUNX1 promotes mitophagy and alleviates pulmonary inflammation during acute lung injury. Signal Transduct. Target. Ther. 8:288. DOI:10.1038/s41392-023-01520-6 [27] Zhou H., Wang X., Xu T., et al. (2024). PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway. Cardiovasc. Res. 121:128−142. DOI:10.1093/cvr/cvae238 [28] Bhatia D., Chung K.P., Nakahira K., et al. (2019). Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis. JCI Insight 4:e132826. DOI:10.1172/jci.insight.132826 [29] Li S., Xu H., Liu S., et al. (2025). Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy. Cell. Mol. Immunol. 22:776−790. DOI:10.1038/s41423-025-01288-5 [30] Sridharan P.S., Koh Y., Miller E., et al. (2024). Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury. Cell Rep. Med. 5:101715. DOI:10.1016/j.xcrm.2024.101715 [31] Ye B., Chen B., Guo C., et al. (2024). C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis. Mol. Ther. 32:1540−1560. DOI:10.1016/j.ymthe.2024.03.003 [32] Chen H., Peng L., Wang Z., et al. (2023). Integrated machine learning and bioinformatic analyses constructed a network between mitochondrial dysfunction and immune microenvironment of periodontitis. Inflammation 46:1932−1951. DOI:10.1007/s10753-023-01851-0 [33] Sun X., Mao Y., Dai P., et al. (2017). Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes. J. Clin. Periodontol. 44:463−471. DOI:10.1111/jcpe.12711 [34] Ma S., He H. and Ren X. (2024). Single-cell and transcriptome analysis of periodontitis: Molecular subtypes and biomarkers linked to mitochondrial dysfunction and immunity. J. Inflamm. Res. 17:11659−11678. DOI:10.2147/jir.s498739 [35] Wankhede N.L., Rajendra Kopalli S., Dhokne M.D., et al. (2024). Decoding mitochondrial quality control mechanisms: Identifying treatment targets for enhanced cellular health. Mitochondrion 78:101926. DOI:10.1016/j.mito.2024.101926 [36] Abu Shelbayeh O., Arroum T., Morris S., et al. (2023). PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants (Basel) 12:1075. DOI:10.3390/antiox12051075 [37] Popov L.D. (2020). Mitochondrial biogenesis: An update. J. Cell Mol. Med. 24:4892−4899. DOI:10.1111/jcmm.15194 [38] Li Y., Feng Y.F., Liu X.T., et al. (2021). Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis. Redox Biol. 38:101771. DOI:10.1016/j.redox.2020.101771 [39] Cheng D., Zhang M., Zheng Y., et al. (2024). α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-PGC-1α/Nrf2 pathway. Redox Biol. 74:103230. DOI:10.1016/j.redox.2024.103230 [40] Wang D., Cao L., Zhou X., et al. (2022). Mitigation of honokiol on fluoride-induced mitochondrial oxidative stress, mitochondrial dysfunction, and cognitive deficits through activating AMPK/PGC-1α/Sirt3. J. Hazard. Mater. 437:129381. DOI:10.1016/j.jhazmat.2022.129381 [41] Hu M., Jiang W., Ye C., et al. (2023). Honokiol attenuates high glucose‐induced peripheral neuropathy via inhibiting ferroptosis and activating AMPK/SIRT1/PGC‐1α pathway in Schwann cells. Phytother. Res. 37:5787−5802. DOI:10.1002/ptr.7984 [42] Yang Y., Qiu W., Xiao J., et al. (2024). Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα-mediated autophagy pathway. J. Transl. Med. 22:309. DOI:10.1186/s12967-024-05060-7 [43] Pang J., Yin L., Jiang W., et al. (2024). Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation. Cell. Signal. 124:111478. DOI:10.1016/j.cellsig.2024.111478 [44] Huang X., Pan L., Zuo Z., et al. (2021). LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling. Nat. Commun. 12:3830. DOI:10.1038/s41467-021-23904-4 [45] Ren J., Xiang B., Song L., et al. (2024). Kaixinsan regulates neuronal mitochondrial homeostasis to improve the cognitive function of Alzheimer's disease by activating CaMKKβ-AMPK-PGC-1α signaling axis. Phytomedicine 135:156170. DOI:10.1016/j.phymed.2024.156170 [46] Zhong J., Dong W., Qin Y., et al. (2020). Roflupram exerts neuroprotection via activation of CREB/PGC‐1α signalling in experimental models of Parkinson's disease. Br. J. Pharmacol. 177:2333−2350. DOI:10.1111/bph.14983 [47] Toyama E.Q., Herzig S., Courchet J., et al. (2016). AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275−281. DOI:10.1126/science.aab4138 [48] Gomes L.C., Benedetto G.D. and Scorrano L. (2011). During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13:589−598. DOI:10.1038/ncb2220 [49] Chan D.C. (2020). Mitochondrial dynamics and its involvement in disease. Annu. Rev. Pathol. 15:235−259. DOI:10.1146/annurev-pathmechdis-012419-032711 [50] Tábara L.C., Burr S.P., Frison M., et al. (2024). MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels. Cell 187:3619−3637.e27. DOI:10.1016/j.cell.2024.05.017 [51] D’Angelo D., Sánchez-Vázquez V.H., Cartes-Saavedra B., et al. (2025). Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB. Nat. Commun. 16:2810. DOI:10.1038/s41467-025-57641-9 [52] Tábara L.C., Segawa M. and Prudent J. (2024). Molecular mechanisms of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 26:123−146. DOI:10.1038/s41580-024-00785-1 [53] Ulecia-Morón C., Bris Á.G., MacDowell K.S., et al. (2025). Chronic mild stress disrupts mitophagy and mitochondrial status in rat frontal cortex. J. Transl. Med. 23:580. DOI:10.1186/s12967-025-06604-1 [54] Qiu J., Yue F., Zhu P., et al. (2023). FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes. Nat. Commun. 14:6344. DOI:10.1038/s41467-023-41988-y [55] Zhang K., Zhang W., Zhang L., et al. (2025). OPA1 mutations in dominant optic atrophy: Domain-specific defects in mitochondrial fusion and apoptotic regulation. J. Transl. Med. 23:471. DOI:10.1186/s12967-025-06471-w [56] Spiegel R., Saada A., Flannery P.J., et al. (2015). Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J. Med. Genet. 53:127−131. DOI:10.1136/jmedgenet-2015-103361 [57] Sun M., Li Y., Xu G., et al. (2024). Sirt3-mediated Opa1 deacetylation protects against sepsis-induced acute lung injury by inhibiting alveolar macrophage pro-inflammatory polarization. Antioxid. Redox Signal. 41:1014−1030. DOI:10.1089/ars.2023.0322 [58] Cho Y. and Kim Y.K. (2024). ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation. Redox Biol. 73:103212. DOI:10.1016/j.redox.2024.103212 [59] König T., Nolte H., Aaltonen M.J., et al. (2021). MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat. Cell Biol. 23:1271−1286. DOI:10.1038/s41556-021-00798-4 [60] Zhao X., Xu H., Li Y., et al. (2022). Silica nanoparticles perturbed mitochondrial dynamics and induced myocardial apoptosis via PKA-DRP1-mitochondrial fission signaling. Sci. Total Environ. 842:156854. DOI:10.1016/j.scitotenv.2022.156854 [61] Wu Q., Liu J., Mao Z., et al. (2022). Ligustilide attenuates ischemic stroke injury by promoting Drp1-mediated mitochondrial fission via activation of AMPK. Phytomedicine 95:153884. DOI:10.1016/j.phymed.2021.153884 [62] Yu R., Liu T., Jin S.B., et al. (2021). MIEF1/2 orchestrate mitochondrial dynamics through direct engagement with both the fission and fusion machineries. BMC Biol. 19:229. DOI:10.1186/s12915-021-01161-7 [63] Su L., Zhang J., Gomez H., et al. (2022). Mitochondria ROS and mitophagy in acute kidney injury. Autophagy 19:401−414. DOI:10.1080/15548627.2022.2084862 [64] Tong M., Mukai R., Mareedu S., et al. (2023). Distinct roles of DRP1 in conventional and alternative mitophagy in obesity cardiomyopathy. Circ. Res. 133:6−21. DOI:10.1161/circresaha.123.322512 [65] Kleele T., Rey T., Winter J., et al. (2021). Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature 593:435−439. DOI:10.1038/s41586-021-03510-6 [66] Fukuda T., Furukawa K., Maruyama T., et al. (2023). The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy. Mol. Cell 83:2045−2058.e9. DOI:10.1016/j.molcel.2023.04.022 [67] Wang S., Long H., Hou L., et al. (2023). The mitophagy pathway and its implications in human diseases. Signal Transduct. Target. Ther. 8:304. DOI:10.1038/s41392-023-01503-7 [68] Yi J., Wang H.L., Lu G., et al. (2024). Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model. Autophagy 20:2655−2676. DOI:10.1080/15548627.2024.2383145 [69] Liu Y., Zhang H., Liu Y., et al. (2023). Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1. Autophagy 19:2443−2463. DOI:10.1080/15548627.2023.2182482 [70] Geisler S., Holmström K.M., Skujat D., et al. (2010). PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12:119−131. DOI:10.1038/ncb2012 [71] Yan C., Gong L., Chen L., et al. (2019). PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 16:419−434. DOI:10.1080/15548627.2019.1628520 [72] Eldeeb M.A., Bayne A.N., Fallahi A., et al. (2024). Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress. Proc. Natl. Acad. Sci. U.S.A. 121:e2313540121. DOI:10.1073/pnas.2313540121 [73] Meissner C., Lorenz H., Hehn B., et al. (2015). Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy. Autophagy 11:1484−1498. DOI:10.1080/15548627.2015.1063763 [74] Wu H. and Chen Q. (2015). Hypoxia activation of mitophagy and its role in disease pathogenesis. Antioxid. Redox Signal. 22:1032−1046. DOI:10.1089/ars.2014.6204 [75] Ma K., Zhang Z., Chang R., et al. (2019). Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. Cell Death Differ. 27:1036−1051. DOI:10.1038/s41418-019-0396-4 [76] Chen G., Han Z., Feng D., et al. (2014). A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol. Cell 54:362−377. DOI:10.1016/j.molcel.2014.02.034 [77] Li E., Li X., Huang J., et al. (2020). BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy. Protein Cell 11:661−679. DOI:10.1007/s13238-020-00713-x [78] Nguyen-Dien G.T., Townsend B., Kulkarni P.G., et al. (2024). PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4. EMBO Rep. 25:3324−3347. DOI:10.1038/s44319-024-00181-y [79] Sun Y., Cao Y., Wan H., et al. (2024). A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass. Mol. Cell 84:327−344.e9. DOI:10.1016/j.molcel.2023.11.038 [80] Delgado J.M., Shepard L.W., Lamson S.W., et al. (2023). The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover. EMBO J. 43:32−60. DOI:10.1038/s44318-023-00006-z [81] Wang J., Fan Y., Luo G., et al. (2025). Nuclear condensates of WW domain-containing adaptor with coiled-coil regulate mitophagy via alternative splicing. Adv. Sci. (Weinh.) 12:2406759. DOI:10.1002/advs.202406759 [82] Cangkrama M., Liu H., Wu X., et al. (2025). MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nat. Cancer 6:1714−1733. DOI:10.1038/s43018-025-01038-6 [83] Xu J., Li Y., Novak C., et al. (2026). Mitochondrial transfer from glia to neurons protects against peripheral neuropathy. Nature 650:951−960. DOI:10.1038/s41586-025-09896-x [84] Borcherding N. and Brestoff J.R. (2023). The power and potential of mitochondria transfer. Nature 623:283−291. DOI:10.1038/s41586-023-06537-z [85] Irwin R.M., Thomas M.A., Fahey M.J., et al. (2024). Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes. Stem Cell Res. Ther. 15:359. DOI:10.1186/s13287-024-03932-9 [86] Chakraborty R., Nonaka T., Hasegawa M., et al. (2023). Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-synuclein and mitochondria. Cell Death Dis. 14:329. DOI:10.1038/s41419-023-05835-8 [87] Novak J., Nahacka Z., Oliveira G.L., et al. (2025). The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models. Cell Rep. 44:115154. DOI:10.1016/j.celrep.2024.115154 [88] Wang Y., Yu H.Y., Yi Z.J., et al. (2025). Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer. Nat. Commun. 16:9448. DOI:10.1038/s41467-025-64486-9 [89] Brestoff J.R., Wilen C.B., Moley J.R., et al. (2021). Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab. 33:270−282.e8. DOI:10.1016/j.cmet.2020.11.008 [90] Ding M., Wang F., Jiang L.L., et al. (2025). LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner. Transl. Neurodegener. 14:64. DOI:10.1186/s40035-025-00525-1 [91] Crewe C., Funcke J.B., Li S., et al. (2021). Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 33:1853−1868.e11. DOI:10.1016/j.cmet.2021.08.002 [92] Lin R.Z., Im G.B., Luo A.C., et al. (2024). Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Nature 629:660−668. DOI:10.1038/s41586-024-07340-0 [93] Mahrouf-Yorgov M., Augeul L., Da Silva C.C., et al. (2017). Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 24:1224−1238. DOI:10.1038/cdd.2017.51 [94] Cai J., Chen Y., She Y., et al. (2024). Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease. Brain Pathol. 35:e13316. DOI:10.1111/bpa.13316 [95] Gao J., Qin A., Liu D., et al. (2019). Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci. Adv. 5:eaaw7215. DOI:10.1126/sciadv.aaw7215 [96] Zhou J., Zhang L., Peng J., et al. (2024). Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation. Cell Metab. 36:2054−2068.e14. DOI:10.1016/j.cmet.2024.05.016 [97] Lu T., Zhang J., Cai J., et al. (2022). Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia–reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps. Biomaterials 284:121486. DOI:10.1016/j.biomaterials.2022.121486 [98] Huang T., Lin R., Su Y., et al. (2023). Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis. Nat. Commun. 14:5781. DOI:10.1038/s41467-023-41529-7 [99] Watson D.C., Bayik D., Storevik S., et al. (2023). GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity. Nat. Cancer 4:648−664. DOI:10.1038/s43018-023-00556-5 [100] Guan F., Wu X., Zhou J., et al. (2024). Mitochondrial transfer in tunneling nanotubes—a new target for cancer therapy. J. Exp. Clin. Cancer Res. 43:147. DOI:10.1186/s13046-024-03069-w [101] Del Vecchio V., Rehman A., Panda S.K., et al. (2024). Mitochondrial transfer from adipose stem cells to breast cancer cells drives multi-drug resistance. J. Exp. Clin. Cancer Res. 43:166. DOI:10.1186/s13046-024-03087-8 [102] Shpilka T. and Haynes C.M. (2017). The mitochondrial UPR: Mechanisms, physiological functions and implications in ageing. Nat. Rev. Mol. Cell Biol. 19:109−120. DOI:10.1038/nrm.2017.110 [103] Inigo J.R. and Chandra D. (2022). The mitochondrial unfolded protein response (UPRmt): Shielding against toxicity to mitochondria in cancer. J. Hematol. Oncol. 15:98. DOI:10.1186/s13045-022-01317-0 [104] Callegari S. and Dennerlein S. (2018). Sensing the stress: A role for the UPRmt and UPRam in the quality control of mitochondria. Front. Cell Dev. Biol. 6:31. DOI:10.3389/fcell.2018.00031 [105] Münch C. and Harper J.W. (2016). Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 534:710−713. DOI:10.1038/nature18302 [106] Li F., Lun D., Liu D., et al. (2023). Melatonin activates mitochondrial unfolded protein response to preserve osteogenic potential of senescent BMSCs via upregulating PDI-6. Biochimie 209:44−51. DOI:10.1016/j.biochi.2023.01.015 [107] Zu X., Chen S., Li Z., et al. (2025). SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis. Bone Res. 13:47. DOI:10.1038/s41413-025-00421-4 [108] Zhou Z., Lu J., Yang M., et al. (2022). The mitochondrial unfolded protein response (UPRmt) protects against osteoarthritis. Exp. Mol. Med. 54:1979−1990. DOI:10.1038/s12276-022-00885-y [109] Wang Y., Jasper H., Toan S., et al. (2021). Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury. Redox Biol. 45:102049. DOI:10.1016/j.redox.2021.102049 [110] Ma T., Xu G., Gao T., et al. (2024). Engineered exosomes with ATF5-modified mRNA loaded in injectable thermogels alleviate osteoarthritis by targeting the mitochondrial unfolded protein response. ACS Appl. Mater. Interfaces 16:21383−21399. DOI:10.1021/acsami.3c17209 [111] Jin Z., Mao Y., Guo Q., et al. (2024). Imbalanced skeletal muscle mitochondrial proteostasis causes bone loss. Research (Wash. D.C.) 7:0465. DOI:10.34133/research.0465 [112] König T. and McBride H.M. (2024). Mitochondrial-derived vesicles in metabolism, disease, and aging. Cell Metab. 36:21−35. DOI:10.1016/j.cmet.2023.11.014 [113] Ryan T.A., Phillips E.O., Collier C.L., et al. (2020). Tollip coordinates parkin‐dependent trafficking of mitochondrial‐derived vesicles. EMBO J. 39:EMBJ2019102539. DOI:10.15252/embj.2019102539 [114] Liu X., Xu L., Song Y., et al. (2024). Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control. Proc. Natl. Acad. Sci. U.S.A. 121:e2217019121. DOI:10.1073/pnas.2217019121 [115] Pan C., Cheng C., Zhong S., et al. (2025). In vitro study on the promotion of osteogenic differentiation by mitochondrial-derived vesicles through activation of inflammation and reprogramming of metabolic pathways. J. Orthop. Surg. Res. 20:388. DOI:10.1186/s13018-025-05749-5 [116] Gu Y., Zhou Q., Sheng S., et al. (2025). Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development. Theranostics 15:10007−10027. DOI:10.7150/thno.111724 [117] Jiao H., Jiang D., Hu X., et al. (2021). Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell 184:2896−2910.e13. DOI:10.1016/j.cell.2021.04.027 [118] Xu Y., Saiding Q., Zhou X., et al. (2025). Promoting mitocytosis via gene-engineered aligned fibers for fascia regeneration. J. Control. Release 382:113725. DOI:10.1016/j.jconrel.2025.113725 [119] Xiang Y., Wang B., Yang W., et al. (2024). Mitocytosis mediated by an enzyme-activable mitochondrion-disturbing polymer-drug conjugate enhances active penetration in glioblastoma therapy. Adv. Mater. 36:2311500. DOI:10.1002/adma.202311500 [120] Hu Y., Lu H., Fang H., et al. (2025). Targeting SIRT3 to regulate mitophagy-dependent ferroptosis for preventing glucocorticoid-induced osteoporosis. Int. J. Surg. 111:6647−6662. DOI:10.1097/js9.0000000000002783 [121] Liu N., Ma Y., Gong W., et al. (2025). Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression. Nat. Commun. 16:4746. DOI:10.1038/s41467-025-59861-5 [122] Lee S.Y., An H.J., Kim J.M., et al. (2021). PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis. Stem Cell Res. Ther. 12:589. DOI:10.1186/s13287-021-02656-4 [123] Li W., Jiang W.S., Su Y.R., et al. (2023). PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products. Cell Death Dis. 14:88. DOI:10.1038/s41419-023-05595-5 [124] Ling Z., Ge X., Jin C., et al. (2025). Copper doped bioactive glass promotes matrix vesicles-mediated biomineralization via osteoblast mitophagy and mitochondrial dynamics during bone regeneration. Bioact. Mater. 46:195−212. DOI:10.1016/j.bioactmat.2024.12.010 [125] Liu J., Zhang X., Hou H., et al. (2024). Advances in osteoblast and mitochondrial dynamics and their transfer in osteoporosis. J. Cell Mol. Med. 28:e70299. DOI:10.1111/jcmm.70299 [126] Chen X.J., Yang Y.Y., Pan Z.C., et al. (2025). The inhibition of PINK1/Drp1-mediated mitophagy by hyperglycemia leads to impaired osteoblastogenesis in diabetes. iScience 28:111519. DOI:10.1016/j.isci.2024.111519 [127] Suh J., Kim N.K., Shim W., et al. (2023). Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis. Cell Metab. 35:345−360.e7. DOI:10.1016/j.cmet.2023.01.003 [128] Qiu Q., Yan X., Zhang Z., et al. (2025). Porphyromonas gingivalis extracellular vesicles exacerbated osteoporosis by disrupting osteoblast mitochondrial dynamics and inhibiting Cpt2-regulated fatty acid oxidation. J. Nanobiotechnology 23:635. DOI:10.1186/s12951-025-03717-z [129] Meng M., Wang J., Wang C., et al. (2023). Coenzyme Q10 protects against hyperlipidemia-induced osteoporosis by improving mitochondrial function via modulating miR-130b-3p/PGC-1α pathway. Calcif. Tissue Int. 114:182−199. DOI:10.1007/s00223-023-01161-5 [130] Yan Z., Zhu S., Wang H., et al. (2019). MOTS-c inhibits osteolysis in the mouse calvaria by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation. Pharmacol. Res. 147:104381. DOI:10.1016/j.phrs.2019.104381 [131] Yu B., Huo L., Liu Y., et al. (2018). PGC-1α controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 23:193−209.e5. DOI:10.1016/j.stem.2018.06.009 [132] Ran D., Zhou D., Liu G., et al. (2023). Reactive oxygen species control osteoblast apoptosis through SIRT1/PGC-1α/P53(Lys382) signaling, mediating the onset of Cd-induced osteoporosis. J. Agric. Food Chem. 71:5991−6002. DOI:10.1021/acs.jafc.2c08505 [133] Ballard A., Zeng R., Zarei A., et al. (2020). The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis. J. Biol. Chem. 295:6629−6640. DOI:10.1074/jbc.ra119.012023 [134] Jeong S., Seong J.H., Kang J.H., et al. (2020). Dynamin‐related protein 1 positively regulates osteoclast differentiation and bone loss. FEBS Lett. 595:58−67. DOI:10.1002/1873-3468.13963 [135] Jang J.S., Hong S.J., Mo S., et al. (2024). PINK1 restrains periodontitis-induced bone loss by preventing osteoclast mitophagy impairment. Redox Biol. 69:103023. DOI:10.1016/j.redox.2023.103023 [136] Ling W., Krager K., Richardson K.K., et al. (2021). Mitochondrial Sirt3 contributes to the bone loss caused by aging or estrogen deficiency. JCI Insight 6:e146728. DOI:10.1172/jci.insight.146728 [137] Zhou R., Wang Y., Liu S., et al. (2025). Brevilin A, a novel BNIP3 inhibitor suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss via impairing mitophagy and mitochondrial metabolism. Phytomedicine 143:156774. DOI:10.1016/j.phymed.2025.156774 [138] Yang Y., Li M., Pan L., et al. (2025). Inhibition of dynamin-related protein 1-dependent mitochondrial fission ameliorates apical periodontitis by attenuating NLRP3 inflammasome-mediated M1 macrophage polarisation. Int. Dent. J. 75:100853. DOI:10.1016/j.identj.2025.100853 [139] Zhu L., Wang Z., Sun X., et al. (2023). STAT3/mitophagy axis coordinates macrophage NLRP3 inflammasome activation and inflammatory bone loss. J. Bone Miner. Res. 38:335−353. DOI:10.1002/jbmr.4756 [140] Wang W., Wang Q., Li W., et al. (2025). Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss. J. Adv. Res. 76:655−668. DOI:10.1016/j.jare.2024.12.033 [141] Chen L., Hu P., Hong X., et al. (2025). Dimethyl fumarate modulates M1/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy. Int. J. Oral Sci. 17:32. DOI:10.1038/s41368-025-00360-0 [142] Cheng S., Zhou L., Wang W.Y., et al. (2025). Mitochondria-loading erythrocytes transfer mitochondria to ameliorate inflammatory bone loss. Acta Biomater. 195:225−239. DOI:10.1016/j.actbio.2025.02.024 [143] Cai W., Zhang J., Yu Y., et al. (2022). Mitochondrial transfer regulates cell fate through metabolic remodeling in osteoporosis. Adv. Sci. (Weinh.) 10:2204871. DOI:10.1002/advs.202204871 [144] Chen M.X., Zhong Y.J., Dong Q.Q., et al. (2021). Global, regional, and national burden of severe periodontitis, 1990–2019: An analysis of the Global Burden of Disease Study 2019. J. Clin. Periodontol. 48:1165−1188. DOI:10.1111/jcpe.13506 [145] Bitencourt F.V., Nascimento G.G., Costa S.A., et al. (2023). Co-occurrence of periodontitis and diabetes-related complications. J. Dent. Res. 102:1088−1097. DOI:10.1177/00220345231179897 [146] Sanz M., Marco del Castillo A., Jepsen S., et al. (2020). Periodontitis and cardiovascular diseases: Consensus report. J. Clin. Periodontol. 47:268−288. DOI:10.1111/jcpe.13189 [147] Sung C.E., Huang R.Y., Cheng W.C., et al. (2019). Association between periodontitis and cognitive impairment: Analysis of national health and nutrition examination survey (NHANES) III. J. Clin. Periodontol. 46:790−798. DOI:10.1111/jcpe.13155 [148] Bosshardt D.D. (2017). The periodontal pocket: Pathogenesis, histopathology and consequences. Periodontol. 2000 76:43–50. DOI:10.1111/prd.12153 [149] Cai X.Y., Zheng C.X., Guo H., et al. (2025). Inflammation-triggered Gli1+ stem cells engage with extracellular vesicles to prime aberrant neutrophils to exacerbate periodontal immunopathology. Cell. Mol. Immunol. 22:371−389. DOI:10.1038/s41423-025-01271-0 [150] Peng X., Cheng L., You Y., et al. (2022). Oral microbiota in human systematic diseases. Int. J. Oral Sci. 14:14. DOI:10.1038/s41368-022-00163-7 [151] Jiang W., Wang Y., Cao Z., et al. (2023). The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy. J. Periodontal Res. 58:853−863. DOI:10.1111/jre.13152 [152] Xu T., Dong Q., Luo Y., et al. (2021). Porphyromonas gingivalis infection promotes mitochondrial dysfunction through Drp1-dependent mitochondrial fission in endothelial cells. Int. J. Oral Sci. 13:28. DOI:10.1038/s41368-021-00134-4 [153] Soliman Wadan A.H., Abdelsattar Ahmed M., Hussein Ahmed A., et al. (2024). The interplay of mitochondrial dysfunction in oral diseases: Recent updates in pathogenesis and therapeutic implications. Mitochondrion 78:101942. DOI:10.1016/j.mito.2024.101942 [154] Liu J., Wang X., Xue F., et al. (2021). Abnormal mitochondrial structure and function are retained in gingival tissues and human gingival fibroblasts from patients with chronic periodontitis. J. Periodontal Res. 57:94−103. DOI:10.1111/jre.12941 [155] Liu M., Shao J., Zhao Y., et al. (2023). Porphyromonas gingivalis evades immune clearance by regulating lysosome efflux. J. Dent. Res. 102:555−564. DOI:10.1177/00220345221146097 [156] Liu J., Zeng J., Wang X., et al. (2018). P53 mediates lipopolysaccharide‐induced inflammation in human gingival fibroblasts. J. Periodontol. 89:1142−1151. DOI:10.1002/jper.18-0026 [157] Liu J., He J., Zhang Z., et al. (2025). Single-cell transcriptomics identifies PDGFRA+ progenitors orchestrating angiogenesis and periodontal tissue regeneration. Int. J. Oral Sci. 17:56. DOI:10.1038/s41368-025-00384-6 [158] He Y., Gan X., Zhang L., et al. (2018). CoCl2 induces apoptosis via a ROS-dependent pathway and Drp1-mediated mitochondria fission in periodontal ligament stem cells. Am. J. Physiol. Cell Physiol. 315:C389−C397. DOI:10.1152/ajpcell.00248.2017 [159] Zhang Z., Cui S., Fu Y., et al. (2023). Mechanical force induces mitophagy-mediated anaerobic oxidation in periodontal ligament stem cells. Cell. Mol. Biol. Lett. 28:57. DOI:10.1186/s11658-023-00453-w [160] Yan J., Yang T., Ma S., et al. (2025). Macrophage-derived mitochondria-rich extracellular vesicles aggravate bone loss in periodontitis by disrupting the mitochondrial dynamics of BMSCs. J. Nanobiotechnology 23:208. DOI:10.1186/s12951-025-03178-4 [161] Liu B., Zhang J., Liu G., et al. (2022). Expression of PINK1 and Parkin in human apical periodontitis. Int. Endod. J. 55:870−881. DOI:10.1111/iej.13760 [162] Zhu C., Zhao Y., Pei D., et al. (2022). PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose. BMC Oral Health 22:144. DOI:10.1186/s12903-022-02167-5 [163] Yan T., Li H., Yan J., et al. (2024). Age‐related mitophagy regulates orthodontic tooth movement by affecting PDLSCs mitochondrial function and RANKL/OPG. FASEB J. 38:e23865. DOI:10.1096/fj.202401280r [164] Aoyama-Ishiwatari S. and Hirabayashi Y. (2021). Endoplasmic reticulum–mitochondria contact sites—emerging intracellular signaling hubs. Front. Cell Dev. Biol. 9:653828. DOI:10.3389/fcell.2021.653828 [165] Aral K., Milward M.R. and Cooper P.R. (2021). Gene expression profiles of mitochondria-endoplasmic reticulum tethering in human gingival fibroblasts in response to periodontal pathogens. Arch. Oral Biol. 128:105173. DOI:10.1016/j.archoralbio.2021.105173 [166] Göbel J., Engelhardt E., Pelzer P., et al. (2020). Mitochondria-endoplasmic reticulum contacts in reactive astrocytes promote vascular remodeling. Cell Metab. 31:791−808.e8. DOI:10.1016/j.cmet.2020.03.005 [167] Dong Q., Luo Y., Yin Y., et al. (2023). RhoA/ROCK1 regulates the mitochondrial dysfunction through Drp1 induced by Porphyromonas gingivalis in endothelial cells. J. Cell Mol. Med. 27:2123−2135. DOI:10.1111/jcmm.17796 [168] Wang J., Chen Y., Yuan H., et al. (2024). Mitochondrial biogenesis disorder and oxidative damage promote refractory apical periodontitis in rat and human. Int. Endod. J. 57:1326−1342. DOI:10.1111/iej.14106 [169] Jin W., Lu D., Wei W., et al. (2025). TSPO participates in the pathogenesis of diabetic periodontitis related to mitophagy. Biochim. Biophys. Acta Mol. Basis Dis. 1871:167866. DOI:10.1016/j.bbadis.2025.167866 [170] Shi L., Ji Y., Zhao S., et al. (2021). Crosstalk between reactive oxygen species and dynamin-related protein 1 in periodontitis. Free Radic. Biol. Med. 172:19−32. DOI:10.1016/j.freeradbiomed.2021.05.031 [171] Morin S.N., Leslie W.D. and Schousboe J.T. (2025). Osteoporosis: A review. JAMA 334:894−907. DOI:10.1001/jama.2025.6003 [172] Saxena Y., Routh S. and Mukhopadhaya A. (2021). Immunoporosis: Role of innate immune cells in osteoporosis. Front. Immunol. 12:687037. DOI:10.3389/fimmu.2021.687037 [173] Yao Y., Cai X., Chen Y., et al. (2024). Estrogen deficiency‐mediated osteoimmunity in postmenopausal osteoporosis. Med. Res. Rev. 45:561−575. DOI:10.1002/med.22081 [174] Fischer V. and Haffner-Luntzer M. (2022). Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin. Cell Dev. Biol. 123:14−21. DOI:10.1016/j.semcdb.2021.05.014 [175] Cheng X., Chen Y., Zhou X., et al. (2025). Immunoporosis: The hidden link between aging immune cells and bone fragility. J. Orthop. Translat. 53:325−335. DOI:10.1016/j.jot.2025.06.015 [176] Tao C., Lin S., Shi Y., et al. (2026). TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy. Innov. Med. 4:100237. DOI:10.59717/j.xinn-med.2026.100237 [177] Ding P., Wang X., Gao C., et al. (2025). RIPK4-mediated MFN2 degradation drives osteogenesis through mitochondrial fragmentation and restricts myelopoiesis by blocking mitochondrial transfer. Nat. Commun. 16:6666. DOI:10.1038/s41467-025-61808-9 [178] Yan C., Shi Y., Yuan L., et al. (2023). Mitochondrial quality control and its role in osteoporosis. Front. Endocrinol. (Lausanne) 14:1077058. DOI:10.3389/fendo.2023.1077058 [179] Xian Y., Liu B., Shen T., et al. (2025). Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus. Bone Res. 13:30. DOI:10.1038/s41413-024-00399-5 [180] Zhang T., Wang L., Duan X., et al. (2024). Sirtuins mediate mitochondrial quality control mechanisms: A novel therapeutic target for osteoporosis. Front. Endocrinol. (Lausanne) 14:1281213. DOI:10.3389/fendo.2023.1281213 [181] Du Z.Y., Zhu H.L., Chang W., et al. (2024). Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle. J. Hazard. Mater. 469:133997. DOI:10.1016/j.jhazmat.2024.133997 [182] Kong X., Shan Z., Zhao Y., et al. (2024). NDR2 is critical for osteoclastogenesis by regulating ULK1-mediated mitophagy. JCI Insight 10:e180409. DOI:10.1172/jci.insight.180409 [183] Hunter D.J. and Bierma-Zeinstra S. (2019). Osteoarthritis. Lancet 393:1745−1759. DOI:10.1016/s0140-6736(19)30417-9 [184] Gao F., Hu Q., Chen W., et al. (2024). Brain regulates weight bearing bone through PGE2 skeletal interoception: Implication of ankle osteoarthritis and pain. Bone Res. 12:16. DOI:10.1038/s41413-024-00316-w [185] Xiang T., Zhang R., Li X., et al. (2026). Hybrid extracellular vesicles drive irreversible mitochondria damage and TCA metabolite deficiency-related chondrocyte senescence. The Innovation 7:101247. DOI:10.1016/j.xinn.2025.101247 [186] Chen Y., Wu Y.Y., Si H.B., et al. (2021). Mechanistic insights into AMPK-SIRT3 positive feedback loop-mediated chondrocyte mitochondrial quality control in osteoarthritis pathogenesis. Pharmacol. Res. 166:105497. DOI:10.1016/j.phrs.2021.105497 [187] Ansari M.Y., Khan N.M., Ahmad I., et al. (2018). Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. Osteoarthritis Cartilage 26:1087−1097. DOI:10.1016/j.joca.2017.07.020 [188] Ansari M.Y., Novak K. and Haqqi T.M. (2022). ERK1/2-mediated activation of DRP1 regulates mitochondrial dynamics and apoptosis in chondrocytes. Osteoarthritis Cartilage 30:315−328. DOI:10.1016/j.joca.2021.11.003 [189] Madhu V., Hernandaz-Meadows M., Coleman A., et al. (2025). The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice. Nat. Commun. 16:5996. DOI:10.1038/s41467-025-60933-9 [190] Ruan S., Tang D., Luo Y., et al. (2024). Identification of mitophagy‐related biomarkers in osteoarthritis. Anim. Models Exp. Med. 7:781−792. DOI:10.1002/ame2.12416 [191] Shao Y., Zhang H., Guan H., et al. (2024). PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function. Bone Res. 12:41. DOI:10.1038/s41413-024-00344-6 [192] Fu B., Shen J., Zou X., et al. (2024). Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Res. 12:32. DOI:10.1038/s41413-024-00333-9 [193] Deng Z., Long D., Li C., et al. (2024). IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2. Bone Res. 12:63. DOI:10.1038/s41413-024-00363-3 [194] Deng Y., Hou M., Wu Y., et al. (2025). SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch. Bone Res. 13:36. DOI:10.1038/s41413-025-00413-4 [195] Hu S.L., Mamun A.A., Shaw J., et al. (2022). TBK1-medicated DRP1 phosphorylation orchestrates mitochondrial dynamics and autophagy activation in osteoarthritis. Acta Pharmacol. Sin. 44:610−621. DOI:10.1038/s41401-022-00967-7 [196] An F., Zhang J., Gao P., et al. (2023). New insight of the pathogenesis in osteoarthritis: The intricate interplay of ferroptosis and autophagy mediated by mitophagy/chaperone-mediated autophagy. Front. Cell Dev. Biol. 11:1297024. DOI:10.3389/fcell.2023.1297024 [197] Ma Y., Song R. and Duan C. (2025). Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation. Front. Immunol. 16:1542369. DOI:10.3389/fimmu.2025.1542369 [198] Ravindran R. and Gustafsson Å.B. (2025). Mitochondrial quality control in cardiomyocytes: Safeguarding the heart against disease and ageing. Nat. Rev. Cardiol. 22:798−813. DOI:10.1038/s41569-025-01142-1 [199] Zhou Y., Wang D., Xiao Q., et al. (2025). Spermidine alleviates diabetic periodontitis by reversing human periodontal ligament stem cell senescence via mitophagy. Free Radic. Biol. Med. 227:379−394. DOI:10.1016/j.freeradbiomed.2024.12.016 [200] Zhu C., Huang K., Li T., et al. (2025). Manganese dioxide coupled metal-organic framework as mitophagy regulator alleviates periodontitis through SIRT1-FOXO3-BNIP3 signaling axis. Biomaterials 319:123179. DOI:10.1016/j.biomaterials.2025.123179 [201] Li X., Zhao Y., Peng H., et al. (2022). Robust intervention for oxidative stress-induced injury in periodontitis via controllably released nanoparticles that regulate the ROS-PINK1-Parkin pathway. Front. Bioeng. Biotechnol. 10:1081977. DOI:10.3389/fbioe.2022.1081977 [202] Chen W., Zhao H. and Li Y. (2023). Mitochondrial dynamics in health and disease: Mechanisms and potential targets. Signal Transduct. Target. Ther. 8:333. DOI:10.1038/s41392-023-01547-9 [203] Joshi A.U., Saw N.L., Vogel H., et al. (2018). Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol. Med. 10:EMMM201708166. DOI:10.15252/emmm.201708166 [204] Dong W.T., Long L.H., Deng Q., et al. (2023). Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice. Nat. Metab. 5:2220−2236. DOI:10.1038/s42255-023-00924-6 [205] Huang J., Xie P., Dong Y., et al. (2020). Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury. Cell Death Differ. 28:1174−1192. DOI:10.1038/s41418-020-00641-7 [206] Chu K., Zhang Z., Chu Y., et al. (2023). Ginsenoside Rg1 alleviates lipopolysaccharide-induced pyroptosis in human periodontal ligament cells via inhibiting Drp1-mediated mitochondrial fission. Arch. Oral Biol. 147:105632. DOI:10.1016/j.archoralbio.2023.105632 [207] Cui L., Chen M., Jin Y., et al. (2024). Mdivi-1 alleviates nicotine-induced human periodontal ligament cells injury by inhibiting mitochondrial fission and dysfunction through the JNK/Drp1 pathway. Ecotoxicol. Environ. Saf. 288:117338. DOI:10.1016/j.ecoenv.2024.117338 [208] Ma S., He H., Ren X., et al. (2025). Luteolin ameliorates periodontitis by modulating mitochondrial dynamics and macrophage polarization via the JAK2/STAT3 pathway. Int. Immunopharmacol. 144:113612. DOI:10.1016/j.intimp.2024.113612 [209] Qian L., Zhu Y., Deng C., et al. (2024). Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. Signal Transduct. Target. Ther. 9:50. DOI:10.1038/s41392-024-01756-w [210] Han B., Jiang W., Liu H., et al. (2020). Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Theranostics 10:2832−2848. DOI:10.7150/thno.37119 [211] Qin X., Jiang M., Zhao Y., et al. (2020). Berberine protects against diabetic kidney disease via promoting PGC‐1α‐regulated mitochondrial energy homeostasis. Br. J. Pharmacol. 177:3646−3661. DOI:10.1111/bph.14935 [212] Xu Z., Li M., Lyu D., et al. (2024). Cinnamaldehyde activates AMPK/PGC-1α pathway via targeting GRK2 to ameliorate heart failure. Phytomedicine 133:155894. DOI:10.1016/j.phymed.2024.155894 [213] Han B., Jiang W., Cui P., et al. (2021). Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation. Genome Med. 13:47. DOI:10.1186/s13073-021-00863-5 [214] Zheng Q., Liu H., Zhang H., et al. (2023). Ameliorating mitochondrial dysfunction of neurons by biomimetic targeting nanoparticles mediated mitochondrial biogenesis to boost the therapy of Parkinson's disease. Adv. Sci. (Weinh.) 10:2300758. DOI:10.1002/advs.202300758 [215] Deng X., He J., Deng W., et al. (2025). Celastrol ameliorates lipopolysaccharide (LPS)-induced acute lung injury by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism. Free Radic. Biol. Med. 227:210−220. DOI:10.1016/j.freeradbiomed.2024.12.017 [216] Sun X., Ping Y., Li X., et al. (2023). Activation of PGC‐1α‐dependent mitochondrial biogenesis supports therapeutic effects of silibinin against type I diabetic periodontitis. J. Clin. Periodontol. 50:964−979. DOI:10.1111/jcpe.13811 [217] Paladines N., Dawson S., Ryan W., et al. (2023). Metabolic reprogramming through mitochondrial biogenesis drives adenosine anti-inflammatory effects: New mechanism controlling gingival fibroblast hyper-inflammatory state. Front. Immunol. 14:1148216. DOI:10.3389/fimmu.2023.1148216 [218] Wang H., Wang X., Ma L., et al. (2022). PGC‐1 alpha regulates mitochondrial biogenesis to ameliorate hypoxia‐inhibited cementoblast mineralization. Ann. N.Y. Acad. Sci. 1516:300−311. DOI:10.1111/nyas.14872 [219] Mendelsohn D.H., Walter N., Cheung W.H., et al. (2025). Targeting mitochondria in bone and cartilage diseases: A narrative review. Redox Biol. 83:103667. DOI:10.1016/j.redox.2025.103667 [220] Li X., Wang J., Zhou X., et al. (2026). Raman spectral fingerprinting links molecular and transcriptomic changes in mesenchymal stem cells during skeletal aging. Dental Res. 1:100003. DOI:10.1016/j.dtrs.2025.100003 [221] Guo Y., Jia X., Cui Y., et al. (2021). Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis. Redox Biol. 41:101915. DOI:10.1016/j.redox.2021.101915 [222] Li M., Yu Y., Xue K., et al. (2023). Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERRα-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats. Redox Biol. 61:102649. DOI:10.1016/j.redox.2023.102649 [223] Li H., Luo D., Xie W., et al. (2024). Irisin reduces senile osteoporosis by inducing osteocyte mitophagy through AMPK activation. iScience 27:111042. DOI:10.1016/j.isci.2024.111042 [224] Chen L., Shi X., Xie J., et al. (2021). Apelin-13 induces mitophagy in bone marrow mesenchymal stem cells to suppress intracellular oxidative stress and ameliorate osteoporosis by activation of AMPK signaling pathway. Free Radic. Biol. Med. 163:356−368. DOI:10.1016/j.freeradbiomed.2020.12.235 [225] Liu F., Yuan Y., Bai L., et al. (2021). LRRc17 controls BMSC senescence via mitophagy and inhibits the therapeutic effect of BMSCs on ovariectomy-induced bone loss. Redox Biol. 43:101963. DOI:10.1016/j.redox.2021.101963 [226] Yang Q., Zou Y., Wei X., et al. (2023). PTP1B knockdown alleviates BMSCs senescence via activating AMPK-mediated mitophagy and promotes osteogenesis in senile osteoporosis. Biochim. Biophys. Acta Mol. Basis Dis. 1869:166795. DOI:10.1016/j.bbadis.2023.166795 [227] Shen Y., Wang H., Xie H., et al. (2024). L-arginine promotes angio-osteogenesis to enhance oxidative stress-inhibited bone formation by ameliorating mitophagy. J. Orthop. Translat. 46:53−64. DOI:10.1016/j.jot.2024.03.003 [228] Ding F., Zhang W., Liu T., et al. (2025). MK-4 ameliorates diabetic osteoporosis in angiogenesis-dependent bone formation by promoting mitophagy in endothelial cells. Drug Des. Devel. Ther. 19:2173−2188. DOI:10.2147/dddt.s503930 [229] Li D., Dai D., Wang J., et al. (2024). Honeycomb bionic graphene oxide quantum dot/layered double hydroxide composite nanocoating promotes osteoporotic bone regeneration via activating mitophagy. Small 20:2403907. DOI:10.1002/smll.202403907 [230] Li Y., Cai Z., Ma W., et al. (2024). A DNA tetrahedron-based ferroptosis-suppressing nanoparticle: Superior delivery of curcumin and alleviation of diabetic osteoporosis. Bone Res. 12:14. DOI:10.1038/s41413-024-00319-7 [231] Han Q., Li J., Deng H., et al. (2025). Tetrahedral framework nucleic acid (tFNA)-loaded metformin (Met) modulates cellular pyroptosis and AMPK to ameliorate type II diabetic periodontitis. Small 21:2411740. DOI:10.1002/smll.202411740 [232] Sarkar J., Das M., Howlader M.S.I., et al. (2022). Epigallocatechin-3-gallate inhibits osteoclastic differentiation by modulating mitophagy and mitochondrial functions. Cell Death Dis. 13:908. DOI:10.1038/s41419-022-05343-1 [233] Lu Z., Jiang L., Lesani P., et al. (2022). Nicotinamide mononucleotide alleviates osteoblast senescence induction and promotes bone healing in osteoporotic mice. J. Gerontol. A Biol. Sci. Med. Sci. 78:186−194. DOI:10.1093/gerona/glac175 [234] Rajput S., Kulkarni C., Sharma S., et al. (2024). Osteogenic effect of an adiponectin-derived short peptide that rebalances bone remodeling: A potential disease-modifying approach for postmenopausal osteoporosis therapy. Arch. Pharm. Res. 47:736−755. DOI:10.1007/s12272-024-01509-x [235] Ono T., Denda R., Tsukahara Y., et al. (2022). Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling. Bone Res. 10:52. DOI:10.1038/s41413-022-00225-w [236] Yuan Y., Yang J., Zhuge A., et al. (2022). Gut microbiota modulates osteoclast glutathione synthesis and mitochondrial biogenesis in mice subjected to ovariectomy. Cell Prolif. 55:e13194. DOI:10.1111/cpr.13194 [237] Ding P., Gao C., Zhou J., et al. (2024). Mitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption. Nat. Commun. 15:5094. DOI:10.1038/s41467-024-49159-3 [238] Zhang M., Sun X., Lu M., et al. (2025). Autophagic-active nanosystem for senile bone regeneration by in-situ mitochondrial biogenesis and intercellular transfer. Bioact. Mater. 53:773−788. DOI:10.1016/j.bioactmat.2025.07.034 [239] Zhou L., He S., Li C., et al. (2025). Two birds with one stone — Semaglutide's impacts on obesity and knee osteoarthritis: From weight loss to pain relief. Innov. Med. 3:100110. DOI:10.59717/j.xinn-med.2025.100110 [240] Chen M., Liu Y., Liu Q., et al. (2025). Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis. Acta Pharm. Sin. B 15:571−591. DOI:10.1016/j.apsb.2024.12.008 [241] Yi G., Li M., Zhou J., et al. (2025). Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment. Mater. Today Bio 32:101697. DOI:10.1016/j.mtbio.2025.101697 [242] Zhuang H., Ren X., Zhang Y., et al. (2024). β‐Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway. Aging Cell 23:e14294. DOI:10.1111/acel.14294 [243] Gou Y., Wang C., Fu K., et al. (2025). Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis. J. Orthop. Translat. 51:242−255. DOI:10.1016/j.jot.2025.01.012 [244] Ye H., Li D., Wei X., et al. (2023). Focused low-intensity pulsed ultrasound alleviates osteoarthritis via restoring impaired FUNDC1-mediated mitophagy. iScience 26:107772. DOI:10.1016/j.isci.2023.107772 [245] Yang J., Zhou Z., Ding X., et al. (2024). Gubi Zhitong formula alleviates osteoarthritis in vitro and in vivo via regulating BNIP3L-mediated mitophagy. Phytomedicine 128:155279. DOI:10.1016/j.phymed.2023.155279 [246] Liu Y., Huang K., Zhou S.L., et al. (2025). Engineered exosomal miR140 modulates mitophagy of chondrocytes through targeting CAPN1 to alleviate osteoarthritis. Sci. China Life Sci. 68:2617−2634. DOI:10.1007/s11427-024-2843-7 [247] Deng Z., Li C., Hu S., et al. (2025). sdRNA-D43 derived from small nucleolar RNA snoRD43 improves chondrocyte senescence and osteoarthritis progression by negatively regulating PINK1/Parkin-mediated mitophagy pathway via dual-targeting NRF1 and WIPI2. Cell Commun. Signal. 23:77. DOI:10.1186/s12964-024-01975-2 [248] Li Q., Gu H., Song K., et al. (2025). Lentinan rewrites extracellular matrix homeostasis by activating mitophagy via mTOR/PINK1/Parkin pathway in cartilage to alleviating osteoarthritis. Int. J. Biol. Macromol. 322:146900. DOI:10.1016/j.ijbiomac.2025.146900 [249] Xia X., Liu Y., Lu Y., et al. (2023). Retuning mitochondrial apoptosis/mitophagy balance via SIRT3-energized and microenvironment-modulated hydrogel microspheres to impede osteoarthritis. Adv. Healthc. Mater. 12:2302475. DOI:10.1002/adhm.202302475 [250] Sun J., Song F.H., Wu J.Y., et al. (2022). Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation. Brain Behav. Immun. 102:53−70. DOI:10.1016/j.bbi.2022.02.015 [251] Li Q., Zhang F., Dai Y., et al. (2024). Activation of the PGC-1α-mediated mitochondrial glutamine metabolism pathway attenuates female offspring osteoarthritis induced by prenatal excessive prednisone. Sci. China Life Sci. 67:2382−2397. DOI:10.1007/s11427-023-2593-4 [252] Kim D., Song J. and Jin E.J. (2021). BNIP3-dependent mitophagy via PGC1α promotes cartilage degradation. Cells 10:1839. DOI:10.3390/cells10071839 [253] Ajmal I., Farooq M.A., Abbas S.Q., et al. (2022). Isoprenaline and salbutamol inhibit pyroptosis and promote mitochondrial biogenesis in arthritic chondrocytes by downregulating β-arrestin and GRK2. Front. Pharmacol. 13:996321. DOI:10.3389/fphar.2022.996321 [254] Lu J., Cai J., Zhou Z., et al. (2025). Gel@CAT-L hydrogel mediates mitochondrial unfolded protein response to regulate reactive oxygen species and mitochondrial homeostasis in osteoarthritis. Biomaterials 321:123283. DOI:10.1016/j.biomaterials.2025.123283 [255] Kornicka-Garbowska K., Groborz S., Lynda B., et al. (2022). Mitochondria transfer restores fibroblasts-like synoviocytes (FLS) plasticity in LPS-induced, in vitro synovitis model. Cell Commun. Signal. 20:137. DOI:10.1186/s12964-022-00923-2 [256] Court A.C., Vega-Letter A.M., Parra-Crisóstomo E., et al. (2024). Mitochondrial transfer balances cell redox, energy and metabolic homeostasis in the osteoarthritic chondrocyte preserving cartilage integrity. Theranostics 14:6471−6486. DOI:10.7150/thno.96723 [257] Kim H.R., Cho H.B., Lee S., et al. (2023). Fusogenic liposomes encapsulating mitochondria as a promising delivery system for osteoarthritis therapy. Biomaterials 302:122350. DOI:10.1016/j.biomaterials.2023.122350 [258] Mei Z., Li H., Huang C., et al. (2025). Extracellular vesicles from adipose-derived stromal/stem cells reprogram dendritic cells to alleviate rat TMJOA by transferring mitochondria. J. Nanobiotechnology 23:389. DOI:10.1186/s12951-025-03478-9 [259] Vega-Letter A.M., García-Guerrero C., Yantén-Fuentes L., et al. (2025). Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis. J. Transl. Med. 23:26. DOI:10.1186/s12967-024-05945-7 [260] Gao J., Hu B., Bao B., et al. (2026). A new perspective on the mechanism exploration and treatment of osteoarthritis. Innov. Med. 4:100203. DOI:10.59717/j.xinn-med.2026.100203 [261] Du M., Gu Y., Xu T., et al. (2025). Healing beyond tradition: Advanced regenerative therapies for joint-related sports injuries. Innov. Med. 3:100132. DOI:10.59717/j.xinn-med.2025.100132 [262] Richardson K.K., Adam G.O., Ling W., et al. (2024). Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice. Mol. Metab. 88:102012. DOI:10.1016/j.molmet.2024.102012 [263] Liu L., Zhang W., Liu T., et al. (2023). The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress. Redox Biol. 62:102663. DOI:10.1016/j.redox.2023.102663 [264] Chen L., Yang J., Cai Z., et al. (2025). Cerium dioxide nanoparticles-based inspector enhances mitochondrial quality control to maintain chondrocyte homeostasis in osteoarthritis therapy. Adv. Healthc. Mater. 14:2405069. DOI:10.1002/adhm.202405069 [265] Chen L., Yang J., Cai Z., et al. (2024). Mitochondrial-oriented injectable hydrogel microspheres maintain homeostasis of chondrocyte metabolism to promote subcellular therapy in osteoarthritis. Research (Wash. D.C.) 7:0306. DOI:10.34133/research.0306 [266] Fan Y., Chen Z., Wang H., et al. (2025). Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis. Bone Res. 13:18. 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Dong Z., Liu C., Li Y., et al. (2026). Mitochondrial quality control as a unifying regulatory platform in inflammatory bone diseases. The Innovation Medicine 4:100255. https://doi.org/10.59717/j.xinn-med.2026.100255
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Dong Z., Liu C., Li Y., et al. (2026). Mitochondrial quality control as a unifying regulatory platform in inflammatory bone diseases. The Innovation Medicine 4:100255. https://doi.org/10.59717/j.xinn-med.2026.100255
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Figure 1.
Molecular mechanisms of mitochondrial quality control (MQC)
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Figure 2.
Regulation of bone cell fate and homeostasis by MQC mechanisms
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Figure 3.
MQC failure as a common pathological axis in inflammatory bone diseases
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Figure 4.
MQC-targeted therapeutic platform for inflammatory bone diseases
