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Mitochondrial transplantation: an overview of a promising therapeutic approach

  • Ji Soo Kim (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Seonha Lee (Department of Functional Genomics, University of Science and Technology (UST) of Korea) ;
  • Won-Kon Kim (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Baek-Soo Han (Department of Functional Genomics, University of Science and Technology (UST) of Korea)
  • Received : 2023.06.02
  • Accepted : 2023.09.04
  • Published : 2023.09.30

Abstract

Mitochondrial transplantation is a promising therapeutic approach for the treatment of mitochondrial diseases caused by mutations in mitochondrial DNA, as well as several metabolic and neurological disorders. Animal studies have shown that mitochondrial transplantation can improve cellular energy metabolism, restore mitochondrial function, and prevent cell death. However, challenges need to be addressed, such as the delivery of functional mitochondria to the correct cells in the body, and the long-term stability and function of the transplanted mitochondria. Researchers are exploring new methods for mitochondrial transplantation, including the use of nanoparticles or CRISPR gene editing. Mechanisms underlying the integration and function of transplanted mitochondria are complex and not fully understood, but research has revealed some key factors that play a role. While the safety and efficacy of mitochondrial transplantation have been investigated in animal models and human trials, more research is needed to optimize delivery methods and evaluate long-term safety and efficacy. Clinical trials using mitochondrial transplantation have shown mixed results, highlighting the need for further research in this area. In conclusion, although mitochondrial transplantation holds significant potential for the treatment of various diseases, more work is needed to overcome challenges and evaluate its safety and efficacy in human trials.

Keywords

Acknowledgement

This research was supported by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5392313) and NRF-2021R1A2C1093421.

References

  1. Bensley RR and Hoerr NL (1934) Studies on cell structure by the freezing-drying method. VI. The preparation and properties of mitochondria. Anat Rec 60, 449-455 https://doi.org/10.1002/ar.1090600408
  2. Ernster L and Schatz G (1981) Mitochondria: a historical review. J Cell Biol 91(3 Pt 2), 227s-255s https://doi.org/10.1083/jcb.91.3.227s
  3. Claude A (1946) Fractionation of mammalian liver cells by differential centrifugation; experimental procedures and results. J Exp Med 84, 61-89 https://doi.org/10.1084/jem.84.1.61
  4. Clark JB and Nicklas WJ (1970) The metabolism of rat brain mitochondria. Preparation and characterization. J Biol Chem 245, 4724-31
  5. Rendon A and Masmoudi A (1985) Purification of non-synaptic and synaptic mitochondria and plasma membranes from rat brain by a rapid Percoll gradient procedure. J Neurosci Methods 14, 41-51 https://doi.org/10.1016/0165-0270(85)90113-X
  6. Sims NR (1990) Rapid isolation of metabolically active mitochondria from rat brain and subregions using Percoll density gradient centrifugation. J Neurochem 55, 698-707 https://doi.org/10.1111/j.1471-4159.1990.tb04189.x
  7. Anderson MF and Sims NR (2000) Improved recovery of highly enriched mitochondrial fractions from small brain tissue samples. Brain Res Brain Res Protoc 5, 95-101 https://doi.org/10.1016/S1385-299X(99)00060-4
  8. Sims NR and Anderson MF (2008) Isolation of mitochondria from rat brain using Percoll density gradient centrifugation. Nat Protoc 3, 1228-1239 https://doi.org/10.1038/nprot.2008.105
  9. Kuznetsov AV, Kunz WS, Saks V et al (2003) Cryopreservation of mitochondria and mitochondrial function in cardiac and skeletal muscle fibers. Anal Biochem 319, 296-303 https://doi.org/10.1016/S0003-2697(03)00326-9
  10. Valenti D, de Bari L, De Filippis B, Ricceri L and Vacca RA (2014) Preservation of mitochondrial functional integrity in mitochondria isolated from small cryopreserved mouse brain areas. Anal Biochem 444, 25-31 https://doi.org/10.1016/j.ab.2013.08.030
  11. Hornig-Do HT, Gunther G, Bust M, Lehnarts P, Bosio A and Wiesner R (2009) Isolation of functional pure mitochondria by superparamagnetic microbeads. Anal Biochem 389, 1-5 https://doi.org/10.1016/j.ab.2009.02.040
  12. Franko A, Baris OR, Bergschneider E et al (2013) Efficient isolation of pure and functional mitochondria from mouse tissues using automated tissue disruption and enrichment with anti-TOM22 magnetic beads. PLoS One 8, e82392
  13. Hebbard WB, Harwood CL, Prajapati P, Springer JE, Saatman KE and Sullivan PG (2019) Fractionated mitochondrial magnetic separation for isolation of synaptic mitochondria from brain tissue. Sci Rep 9, 9656
  14. Chen WW, Freinkman E, Wang T, Birsoy K and Sabatini DM (2016) Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166, 1324-1337 e11
  15. Ahier A, Dai CY, Tweedie A, Bezawork-Geleta A, Kirmes I and Zuryn S (2018) Affinity purification of cell-specific mitochondria from whole animals resolves patterns of genetic mosaicism. Nat Cell Biol 20, 352-360 https://doi.org/10.1038/s41556-017-0023-x
  16. Jiang D, Gao F, Zhang Y et al (2016) Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Dis 7, e2467
  17. Li CJ, Chen PK, Sun LY and Pang CY (2017) Enhancement of mitochondrial transfer by antioxidants in human mesenchymal stem cells. Oxid Med Cell Longev 2017, 8510805
  18. Pasquier J, Guerrouahen BS, Al Thawadi H et al (2013) Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med 11, 94
  19. Moschoi R, Imbert V, Nebout M et al (2016) Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood 128, 253-264 https://doi.org/10.1182/blood-2015-07-655860
  20. Lou E, Fujisawa S, Morozov A et al (2012) Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS One 7, e33093
  21. Lu J, Zheng X, Li F et al (2017) Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells. Oncotarget 8, 15539-15552 https://doi.org/10.18632/oncotarget.14695
  22. Lin HY, Liou CW, Chen SD et al (2015) Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. Mitochondrion 22, 31-44 https://doi.org/10.1016/j.mito.2015.02.006
  23. Koyanagi M, Brandes RP, Haendeler J, Zeiher AM and Dimmeler S (2005) Cell-to-cell connection of endothelial progenitor cells with cardiac myocytes by nanotubes: a novel mechanism for cell fate changes? Circ Res 96, 1039-1041 https://doi.org/10.1161/01.RES.0000168650.23479.0c
  24. Onfelt B, Nedvetzki S, Benninger RK et al (2006) Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. J Immunol 12, 8476-8483 https://doi.org/10.4049/jimmunol.177.12.8476
  25. Acquistapace A, Bru T, Lesault PF et al (2011) Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 29, 812-824 https://doi.org/10.1002/stem.632
  26. Liu K, Ji K, Guo L et al (2014) Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res 92, 10-18 https://doi.org/10.1016/j.mvr.2014.01.008
  27. Jackson MV, Morrison TJ, Doherty DF et al (2016) Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells 34, 2210-2223 https://doi.org/10.1002/stem.2372
  28. Spees JL, Olson SD, Whitney MJ and Prockop DJ (2006) Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A 103,1283-1288 https://doi.org/10.1073/pnas.0510511103
  29. Sinclair KA, Yerkovich ST, Hopkins PM and Chambers DC (2016) Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Res Ther 7, 91
  30. Ali Pour P, Kenney MC and Kheradvar A (2020) Bioenergetics consequences of mitochondrial transplantation in cardiomyocytes. J Am Heart Assoc 9, e014501
  31. Zhang A, Liu Y, Pan J et al (2023) Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance. Mol Ther 31, 1468-1479 https://doi.org/10.1016/j.ymthe.2023.02.016
  32. Sun X, Chen H, Gao R et al (2023) Intravenous transplantation of an ischemic-specific peptide-TPP-mitochondrial compound alleviates myocardial ischemic reperfusion injury. ACS Nano 17, 896-909 https://doi.org/10.1021/acsnano.2c05286
  33. Gao J, Qin A, Liu D et al (2019) Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network. Sci Adv 5, eaaw7215
  34. Rafelski SM (2013) Mitochondrial network morphology: building an integrative, geometrical view. BMC Biol 11, 71
  35. Kesner EE, Saada-Reich A and Lorberboum-Galski H (2016) Characteristics of mitochondrial transformation into human cells. Sci Rep 6, 26057
  36. Lee JM, Hwang JW, Kim MJ et al (2021) Mitochondrial transplantation modulates inflammation and apoptosis, alleviating tendinopathy both in vivo and in vitro. Antioxidants (Basel) 10, 696
  37. Chang JC, Wu SL, Liu KH et al (2016) Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson's disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res 170, 40-56 e43
  38. Shi X, Zhao M, Fu C and Fu A (2017) Intravenous administration of mitochondria for treating experimental Parkinson's disease. Mitochondrion 34, 91-100 https://doi.org/10.1016/j.mito.2017.02.005
  39. Wong RCB, Lim SY, Hung SSC et al (2017) Mitochondrial replacement in an iPSC model of Leber's hereditary optic neuropathy. Aging (Albany NY) 9, 1341-1350 https://doi.org/10.18632/aging.101231
  40. Zhang TG and Miao CY (2023) Mitochondrial transplantation as a promising therapy for mitochondrial diseases. Acta Pharm Sin B 13, 1028-1035 https://doi.org/10.1016/j.apsb.2022.10.008
  41. Caicedo A, Fritz V, Brondello JM et al (2015) MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 5, 9073
  42. Guariento A, Piekarski BL, Doulamis IP et al (2021) Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J Thorac Cardiovasc Surg 162, 992-1001 https://doi.org/10.1016/j.jtcvs.2020.10.151
  43. Kim MJ, Hwang JW, Yun CK, Lee Y and Choi YS (2018) Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep 8, 3330
  44. Macheiner T, Fengler VH, Agreiter M et al (2016) Magnetomitotransfer: an efficient way for direct mitochondria transfer into cultured human cells. Sci Rep 6, 35571
  45. Chang JC, Liu KH, Li YC et al (2013) Functional recovery of human cells harbouring the mitochondrial DNA mutation MERRF A8344G via peptide-mediated mitochondrial delivery. Neurosignals 21, 160-173 https://doi.org/10.1159/000341981
  46. Wu S, Zhang A, Li S et al (2018) Polymer functionalization of isolated mitochondria for cellular transplantation and metabolic phenotype alteration. Adv Sci (Weinh) 5, 1700530
  47. Wu TH, Sagullo E, Case D et al (2016) Mitochondrial transfer by photothermal nanoblade restores metabolite profile in mammalian cells. Cell Metab 23, 921-929 https://doi.org/10.1016/j.cmet.2016.04.007
  48. Gabelein CG, Feng Q, Sarajlic E et al (2022) Mitochondria transplantation between living cells. PLoS Biol 20, e3001576
  49. Emani SM, Piekarski BL, Harrild D, Del Nido PJ and McCully JD (2017) Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg 154, 286-289 https://doi.org/10.1016/j.jtcvs.2017.02.018
  50. Park A, Oh M, Lee SJ et al (2021) Mitochondrial transplantation as a novel therapeutic strategy for mitochondrial diseases. Int J Mol Sci 22, 4793