Mitochondrial components transferred by MSC-derived exosomes promoted bone regeneration under high salt microenvironment via DRP1/Wnt signaling

Titze, J.; Luft, F. C. Speculations on salt and the genesis of arterial hypertension. Kidney Int. 2017, 91, 1324–1335.

Cheng, Y.; Song, H. Y.; Pan, X. Q.; Xue, H.; Wan, Y. F.; Wang, T.; Tian, Z. M.; Hou, E. T.; Lanza, I. R.; Liu, P. Y. et al. Urinary metabolites associated with blood pressure on a low- or high-sodium diet. Theranostics 2018, 8, 1468–1480.

Malta, D.; Petersen, K. S.; Johnson, C.; Trieu, K.; Rae, S.; Jefferson, K.; Santos, J. A.; Wong, M. M. Y.; Raj, T. S.; Webster, J. et al. High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017). J. Clin. Hypertens. 2018, 20, 1654–1665.

Patel, Y.; Joseph, J. Sodium intake and heart failure. Int. J. Mol. Sci. 2020, 21, 9474.

Micha, R.; Shulkin, M. L.; Peñalvo, J. L.; Khatibzadeh, S.; Singh, G. M.; Rao, M.; Fahimi, S.; Powles, J.; Mozaffarian, D. Etiologic effects and optimal intakes of foods and nutrients for risk of cardiovascular diseases and diabetes: Systematic reviews and meta-analyses from the Nutrition and Chronic Diseases Expert Group (NutriCoDE). PLoS One 2017, 12, e0175149.

Na, S. Y.; Janakiraman, M.; Leliavski, A.; Krishnamoorthy, G. High-salt diet suppresses autoimmune demyelination by regulating the blood–brain barrier permeability. Proc. Natl. Acad. Sci. USA 2021, 118, e2025944118.

Schröder, A.; Neubert, P.; Titze, J.; Bozec, A.; Neuhofer, W.; Proff, P.; Kirschneck, C.; Jantsch, J. Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5. JCI Insight 2019, 4, e127868.

Paddenberg, E.; Krenmayr, B.; Jantsch, J.; Kirschneck, C.; Proff, P.; Schröder, A. Dietary salt and myeloid NFAT5 (nuclear factor of activated T cells 5) impact on the number of bone-remodelling cells and frequency of root resorption during orthodontic tooth movement. Ann. Anat. 2022, 244, 151979.

Shum, L. C.; White, N. S.; Mills, B. N.; de Mesy Bentley, K. L.; Eliseev, R. A. Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev. 2016, 25, 114–122.

Chan, D. C. Fusion and fission: Interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 2012, 46, 265–287.

Jeong, S.; Seong, J. H.; Kang, J. H.; Lee, D. S.; Yim, M. Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss. FEBS Lett. 2021, 595, 58–67.

Ma, T. Y.; Lin, S. Y.; Wang, B.; Wang, Q. R.; Xia, W. J.; Zhang, H. X.; Cui, Y. T.; He, C. K.; Wu, H.; Sun, F. et al. TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction. Biochem. Biophys. Res. Commun. 2019, 519, 674–681.

Lang, H. M.; Li, Q.; Yu, H.; Li, P.; Lu, Z. S.; Xiong, S. Q.; Yang, T.; Zhao, Y.; Huang, X. H.; Gao, P. et al. Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function. Br. J. Pharmacol. 2015, 172, 5548–5558.

Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J. J.; Lötvall, J. O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659.

Xia, L. J.; Zhang, C. L.; Lv, N. Y.; Liang, Z. H.; Ma, T. H.; Cheng, H. B.; Xia, Y. B.; Shi, L. Y. AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages. Theranostics 2022, 12, 2928–2947.

Gurung, S.; Perocheau, D.; Touramanidou, L.; Baruteau, J. The exosome journey: From biogenesis to uptake and intracellular signalling. Cell Commun. Signal. 2021, 19, 47.

Narayanan, R.; Huang, C. C.; Ravindran, S. Hijacking the cellular mail: Exosome mediated differentiation of mesenchymal stem cells. Stem Cells Int. 2016, 2016, 3808674.

Guescini, M.; Genedani, S.; Stocchi, V.; Agnati, L. F. Astrocytes and glioblastoma cells release exosomes carrying mtDNA. J. Neural Transm. 2010, 117, 1–4.

Dave, K. M.; Stolz, D. B.; Manickam, D. S. Delivery of mitochondria-containing extracellular vesicles to the BBB for ischemic stroke therapy. Expert Opin. Drug Deliv. 2023, 20, 1769–1788.

Hu, M. Y.; Lin, Y. Y.; Men, X. J.; Wang, S. S.; Sun, X. B.; Zhu, Q.; Lu, D. L.; Liu, S. X.; Zhang, B. J.; Cai, W. et al. High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke. J. Neuroinflammation 2021, 18, 90.

Schröder, A.; Gubernator, J.; Leikam, A.; Nazet, U.; Cieplik, F.; Jantsch, J.; Neubert, P.; Titze, J.; Proff, P.; Kirschneck, C. Dietary salt accelerates orthodontic tooth movement by increased osteoclast activity. Int. J. Mol. Sci. 2021, 22, 596.

Kleinewietfeld, M.; Manzel, A.; Titze, J.; Kvakan, H.; Yosef, N.; Linker, R. A.; Muller, D. N.; Hafler, D. A. Sodium chloride drives autoimmune disease by the induction of pathogenic T_H17 cells. Nature 2013, 496, 518–522.

Côrte-Real, B. F.; Hamad, I.; Hornero, R. A.; Geisberger, S.; Roels, J.; Van Zeebroeck, L.; Dyczko, A.; van Gisbergen, M. W.; Kurniawan, H.; Wagner, A. et al. Sodium perturbs mitochondrial respiration and induces dysfunctional Tregs. Cell Metab. 2023, 35, 299–315.e8.

Mazzitelli, I.; Bleichmar, L.; Melucci, C.; Gerber, P. P.; Toscanini, A.; Cuestas, M. L.; Diaz, F. E.; Geffner, J. High salt induces a delayed activation of human neutrophils. Front. Immunol. 2022, 13, 831844.

Geisberger, S.; Bartolomaeus, H.; Neubert, P.; Willebrand, R.; Zasada, C.; Bartolomaeus, T.; McParland, V.; Swinnen, D.; Geuzens, A.; Maifeld, A. et al. Salt transiently inhibits mitochondrial energetics in mononuclear phagocytes. Circulation 2021, 144, 144–158.

Li, Y. H.; Xu, F.; Thome, R.; Guo, M. F.; Sun, M. L.; Song, G. B.; Li, R. L.; Chai, Z.; Ciric, B.; Rostami, A. M. et al. Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis. J. Neuroinflammation 2019, 16, 149.

Zhou, Y. K.; Han, C. S.; Zhu, Z. L.; Chen, P.; Wang, Y. M.; Lin, S.; Chen, L. J.; Zhuang, Z. M.; Zhou, Y. H.; Yang, R. L. M2 exosomes modified by hydrogen sulfide promoted bone regeneration by moesin mediated endocytosis. Bioact. Mater. 2024, 31, 192–205.

Bonekamp, N. A.; Peter, B.; Hillen, H. S.; Felser, A.; Bergbrede, T.; Choidas, A.; Horn, M.; Unger, A.; Di Lucrezia, R.; Atanassov, I. et al. Small-molecule inhibitors of human mitochondrial DNA transcription. Nature 2020, 588, 712–716.

Li, L. L.; Lai, E. Y.; Luo, Z. M.; Solis, G.; Mendonca, M.; Griendling, K. K.; Wellstein, A.; Welch, W. J.; Wilcox, C. S. High salt enhances reactive oxygen species and angiotensin II contractions of glomerular afferent arterioles from mice with reduced renal mass. Hypertension 2018, 72, 1208–1216.

Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002, 360, 1903–1913.

Takase, H.; Takeuchi, Y.; Fujita, T.; Ohishi, T. Excessive salt intake reduces bone density in the general female population. Eur. J. Clin. Invest. 2023, 53, e14034.

Cui, Y.; Sun, K. H.; Xiao, Y. W.; Li, X. Y.; Mo, S.; Yuan, Y. H.; Wang, P. P.; Yang, L.; Zhang, R. H.; Zhu, X. F. High-salt diet accelerates bone loss accompanied by activation of ion channels related to kidney and bone tissue in ovariectomized rats. Ecotoxicol. Environ. Saf. 2022, 244, 114024.

Mishra, P.; Chan, D. C. Metabolic regulation of mitochondrial dynamics. J. Cell. Biol. 2016, 212, 379–387.

Chang, M. H.; Song, X. G.; Geng, X. R.; Wang, X. W.; Wang, W. J.; Chen, T. C.; Xie, L.; Song, X. R. Temozolomide–perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in non-small cell lung cancer cells and sensitizes them to irradiation. J. Exp. Clin. Cancer Res. 2018, 37, 250.

Gan, X. Q.; Huang, S. B.; Yu, Q.; Yu, H. Y.; Yan, S. S. Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction. Biochem. Biophys. Res. Commun. 2015, 468, 719–725.

Suh, J.; Kim, N. K.; Shim, W.; Lee, S. H.; Kim, H. J.; Moon, E.; Sesaki, H.; Jang, J. H.; Kim, J. E.; Lee, Y. S. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis. Cell Metab. 2023, 35, 345–360.e7.

Li, L.; Peng, X. Z.; Qin, Y. B.; Wang, R. C.; Tang, J. L.; Cui, X.; Wang, T.; Liu, W. L.; Pan, H. B.; Li, B. Acceleration of bone regeneration by activating Wnt/β-catenin signalling pathway via lithium released from lithium chloride/calcium phosphate cement in osteoporosis. Sci. Rep. 2017, 7, 45204.

Shares, B. H.; Busch, M.; White, N.; Shum, L.; Eliseev, R. A. Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation. J. Biol. Chem. 2018, 293, 16019–16027.

Xiong, X. P.; Hasani, S.; Young, L. E. A.; Rivas, D. R.; Skaggs, A. T.; Martinez, R.; Wang, C.; Weiss, H. L.; Gentry, M. S.; Sun, R. C. et al. Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer. Cell Death Differ. 2022, 29, 1913–1927.

Chen, J.; Sun, W. W.; Zhang, H. F.; Ma, J. W.; Xu, P. W.; Yu, Y. D.; Fang, H. Q.; Zhou, L.; Lv, J. D.; Xie, J. et al. Macrophages reprogrammed by lung cancer microparticles promote tumor development via release of IL-1β. Cell. Mol. Immunol. 2020, 17, 1233–1244.

Ikeda, G.; Santoso, M. R.; Tada, Y.; Li, A. M.; Vaskova, E.; Jung, J. H.; O’Brien, C.; Egan, E.; Ye, J. B.; Yang, P. C. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J. Am. Coll. Cardiol. 2021, 77, 1073–1088.