The Role of Mitochondrial Permeability Transition in Bone Metabolism, Bone Healing, and Bone Diseases

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2024 Oct 26

PMID 39456250

Authors

Xiting Zhu

Ziqi Qin

Min Zhou

Chen Li

Junjun Jing

Wushuang Ye

Xueqi Gan

Affiliations

Soon will be listed here.

Abstract

Bone is a dynamic organ with an active metabolism and high sensitivity to mitochondrial dysfunction. The mitochondrial permeability transition pore (mPTP) is a low-selectivity channel situated in the inner mitochondrial membrane (IMM), permitting the exchange of molecules of up to 1.5 kDa in and out of the IMM. Recent studies have highlighted the critical role of the mPTP in bone tissue, but there is currently a lack of reviews concerning this topic. This review discusses the structure and function of the mPTP and its impact on bone-related cells and bone-related pathological states. The mPTP activity is reduced during the osteogenic differentiation of mesenchymal stem cells (MSCs), while its desensitisation may underlie the mechanism of enhanced resistance to apoptosis in neoplastic osteoblastic cells. mPTP over-opening triggers mitochondrial swelling, regulated cell death, and inflammatory response. In particular, mPTP over-opening is involved in dexamethasone-induced osteoblast dysfunction and bisphosphonate-induced osteoclast apoptosis. In vivo, the mPTP plays a significant role in maintaining bone homeostasis, with many bone disorders linked to its excessive opening. Genetic deletion or pharmacological inhibition of the over-opening of mPTP has shown potential in enhancing bone injury recovery and alleviating bone diseases. Here, we review the findings on the relationship of the mPTP and bone at both the cellular and disease levels, highlighting novel avenues for pharmacological approaches targeting mitochondrial function to promote bone healing and manage bone-related disorders.

References

Guo Y, Su T, Yang M, Li C, Guo Q, Xiao Y . The role of autophagy in bone homeostasis. J Cell Physiol. 2021; 236(6):4152-4173. DOI: 10.1002/jcp.30111. View

Cao C, Chen S, Song Z, Liu Z, Zhang M, Ma Z . Inflammatory Stimulation Mediates Nucleus Pulposus Cell Necroptosis Through Mitochondrial Function Disfunction and Oxidative Stress Pathway. Front Biosci (Landmark Ed). 2022; 27(4):111. DOI: 10.31083/j.fbl2704111. View

Saunders R, Szymczyk K, Shapiro I, Adams C . Matrix regulation of skeletal cell apoptosis III: mechanism of ion pair-induced apoptosis. J Cell Biochem. 2006; 100(3):703-15. DOI: 10.1002/jcb.21001. View

Gan X, Zhang L, Liu B, Zhu Z, He Y, Chen J . CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation. J Physiol Biochem. 2018; 74(3):395-402. DOI: 10.1007/s13105-018-0627-z. View

Waqas K, Muller M, Koedam M, El Kadi Y, Zillikens M, van der Eerden B . Methylglyoxal - an advanced glycation end products (AGEs) precursor - Inhibits differentiation of human MSC-derived osteoblasts in vitro independently of receptor for AGEs (RAGE). Bone. 2022; 164:116526. DOI: 10.1016/j.bone.2022.116526. View

Tanaka T, Saotome M, Katoh H, Satoh T, Hasan P, Ohtani H . Glycogen synthase kinase-3β opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation. J Physiol Sci. 2018; 68(6):865-871. PMC: 10717190. DOI: 10.1007/s12576-018-0611-y. View

Bonora M, Giorgi C, Pinton P . Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol. 2021; 23(4):266-285. DOI: 10.1038/s41580-021-00433-y. View

Sun J, Hou Y, Fu X, Fu X, Ma J, Yang M . Selenium-Containing Protein From Selenium-Enriched Attenuates Cisplatin-Induced Apoptosis in MC3T3-E1 Mouse Preosteoblast by Inhibiting Mitochondrial Dysfunction and ROS-Mediated Oxidative Damage. Front Physiol. 2019; 9:1907. PMC: 6333850. DOI: 10.3389/fphys.2018.01907. View

Wei K, Chen T, Fang H, Shen X, Tang Z, Zhao J . Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease. Cell Commun Signal. 2024; 22(1):328. PMC: 11177463. DOI: 10.1186/s12964-024-01677-9. View

10.

Agarwal A, Wu P, Hughes E, Fukaya M, Tischfield M, Langseth A . Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes. Neuron. 2017; 93(3):587-605.e7. PMC: 5308886. DOI: 10.1016/j.neuron.2016.12.034. View

11.

Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M . Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A. 2013; 110(15):5887-92. PMC: 3625323. DOI: 10.1073/pnas.1217823110. View

12.

Jahandiez V, Cour M, Bochaton T, Abrial M, Loufouat J, Gharib A . Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition. Basic Res Cardiol. 2017; 112(4):35. DOI: 10.1007/s00395-017-0624-3. View

13.

Mendoza A, Patel P, Robichaux D, Ramirez D, Karch J . Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury. Circ Res. 2024; 134(10):1292-1305. PMC: 11081482. DOI: 10.1161/CIRCRESAHA.123.323882. View

14.

Ying Z, Xiang G, Zheng L, Tang H, Duan L, Lin X . Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming. Cell Metab. 2019; 29(2):502. DOI: 10.1016/j.cmet.2018.12.017. View

15.

Lingan J, Alanzalon R, Porter Jr G . Preventing permeability transition pore opening increases mitochondrial maturation, myocyte differentiation and cardiac function in the neonatal mouse heart. Pediatr Res. 2017; 81(6):932-941. DOI: 10.1038/pr.2017.19. View

16.

He P, Liu F, Li M, Ren M, Wang X, Deng Y . Mitochondrial Calcium Ion Nanogluttons Alleviate Periodontitis via Controlling mPTPs. Adv Healthc Mater. 2023; 12(15):e2203106. DOI: 10.1002/adhm.202203106. View

17.

Jang H, Noh M, Jung E, Kim W, Southekal S, Guda C . Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury. Kidney Int. 2019; 97(2):327-339. PMC: 6983334. DOI: 10.1016/j.kint.2019.08.019. View

18.

Yu C, Davidson S, Harapas C, Hilton J, Mlodzianoski M, Laohamonthonkul P . TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020; 183(3):636-649.e18. PMC: 7599077. DOI: 10.1016/j.cell.2020.09.020. View

19.

Xu W, Che Y, Zhang Q, Huang H, Ding C, Wang Y . Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition. Cell Metab. 2020; 33(2):424-436.e10. DOI: 10.1016/j.cmet.2020.11.018. View

20.

Dumbali S, Horton P, Moore T, Wenzel P . Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors. Commun Biol. 2024; 7(1):967. PMC: 11316084. DOI: 10.1038/s42003-024-06671-y. View