Abstract
Mitochondria play a key role in cellular energy production and contribute to cell metabolism, homeostasis, intracellular signalling and organelle’s quality control, among other roles. Viable, respiratory-competent mitochondria exist also outside the cells. Such extracellular/exogenous mitochondria occur in the bloodstream, being released by platelets, activated monocytes and endothelial progenitor cells. In the nervous system, the cerebrospinal fluid contains mitochondria discharged by astrocytes. Various pathologies, including the cardiovascular and neurodegenerative diseases, are associated with mitochondrial dysfunction. A strategy to reverse dysfunction and restore cell normality is the transplantation of mitochondria (freshly isolated from a healthy tissue) into the zone at risk, such as the ischemic heart and/or damaged nervous tissue. The functional exogenous mitochondria will replace the harmed ones, ensuing cardioprotective and neuroprotective effects. The diversity of transplantation settings (in vitro, in animal models and patients) offered variable answers (including lack of consensus) on efficacy of this strategy. Therefore, a critical overview of the current and future trends in mitochondrial transplantation seems to be required. Here, we outline the recent developments on (i) extracellular mitochondria types and roles, (ii) transplantation protocols, (iii) mechanisms of mitochondrial incorporation, (iv) the benefit of extracellular mitochondria transplantation in human health and diseases and (v) open questions that deserve urgent answers.
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References
Ali Pour P, Kenney MC, Kheradvar A (2020) Bioenergetics consequences of mitochondrial transplantation in cardiomyocytes. J Am Heart Assoc 9(7):e014501. https://doi.org/10.1161/JAHA.119.014501
Babenko VA, Silachev DN, Popkov VA, Zorova LD, Pevzner IB, Plotnikov EY, Sukhikh GT, Zorov D (2018) Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules 23:687. https://doi.org/10.3390/molecules23030687
Bertero E, Maack C, O’Rourke B (2018) Mitochondrial transplantation in humans: “magical” cure or cause for concern? J Clin Invest 128:5191–5194. https://doi.org/10.1172/JCI124944
Berridge MV, Neuzil J (2017) The mobility of mitochondria: Intercellular trafficking in health and disease. Clin Exp Pharmacol Physiol 44. Suppl 1:15–20. https://doi.org/10.1111/1440-1681.12764
Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, Paré A, Rousseau M, Naika GS, Lévesque T, Laflamme C, Marcoux G, Lambeau G, Farndale RW, Pouliot M, Hamzeh-Cognasse H, Cognasse F, Garraud O, Nigrovic PA, Guderley H, Lacroix S, Thibault L, Semple JW, Gelb MH, Boilard E (2014) Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124:2173–2183. https://doi.org/10.1182/blood-2014-05-573543
Caicedo A, Aponte PM, Cabrera F, Carmen Hidalgo, Khoury M (2017) Artificial mitochondria transfer: current challenges, advances, and future applications. Stem Cells Int 7610414. https://doi.org/10.1155/2017/7610414
Chang JC, Liu KH, Li YC, Kou SJ, Wei YH, Chuang CS, Hsieh M, Liu CS (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
Chang JC, Wu SL, Liu KH, Chen YH, Chuang CS, Cheng FC, Su HL, Wei YH, Kuo SJ, Liu CS (2016) Allogeneic/ xenogeneic transplantation of peptide–labelled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6–hydroxydopamine–induced neurotoxicity. Transl Res 170(40–56):e3. https://doi.org/10.1016/j.trsl.2015.12.003
Chang CY, Liang MZ, Chen L (2019) Current progress of mitochondrial transplantation that promotes neuronal regeneration. Transl Neurodegener 8:17. https://doi.org/10.1186/s40035-019-0158-8
Chernyak BV (2020) Mitochondrial transplantation: a critical analysis. Biochemistry (Mosc). 85:636–641. https://doi.org/10.1134/S0006297920050132
Chou SHY, Lan J, Esposito E, Ning MM, Balaj L, Ji X, Lo EH, Hayakawa K (2017) Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke 48:2231–2237. https://doi.org/10.1161/STROKEAHA.117.017758
Cowan DB, Yao R, Akurathi V, Snay ER, Thedsanamoorthy JK, Zurakowski D, Ericsson M, Friehs I, Wu Y, Levitsky S, Del Nido PJ, Packard AB, McCully JD (2016) Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 11(8):e0160889. https://doi.org/10.1371/journal.pone.0160889
Cowan DB, Yao R, Thedsanamoorthy JK, Zurakowski D, Del Nido PJ, McCully JD (2017) Transit and integration of extracellular mitochondria in human heart cells. Sci Rep 7:17450. https://doi.org/10.1038/s41598-017-17813-0
Al DZ, Amir OA, Tanos R, Pastor B, Meddeb R, Sanchez C, Arena G, Lasorsa L, Bennett A, Grange T, El Messaoudi S, Mazard T, Prevostel C, Thierry AR (2020) Blood contains circulating cell-free respiratory competent mitochondria. FASEB J 34:3616–3630. https://doi.org/10.1096/fj.201901917RR
Emani SM, Piekarski BL, Harrild D, del Nido PJ, 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
Emani SM, McCully JD (2018) Mitochondrial transplantation: applications for paediatric patients with congenital heart disease. Transl Pediatr 7:169–175. https://doi.org/10.21037/tp.2018.02.02
Gollihue JL, Patel SP, Eldahan KC, Cox DH, Donahue RR, Taylor BK, Sullivan PG, Rabchevsky AG (2018) Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma 35:1800–1818. https://doi.org/10.1089/neu.2017.5605
Hammel JM (2017) Mitochondrial autotransplantation: a “shoot” in the dark? J Thor and Cardiovasc Surgery 154:290. https://doi.org/10.1016/j.jtcvs.2017.03.061
Hayakawa K, Esposito E, Wang X, Terasaki Y, Yi L, Xing C, Ji X, Lo EH (2017) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535(7613):551–555. https://doi.org/10.1038/nature18928
Hayakawa K, Bruzzese M, Chou SH, Ning M, Ji X, Lo EH (2018) Extracellular mitochondria for therapy and diagnosis in acute central nervous system injury. JAMA Neurol 75:119–122. https://doi.org/10.1001/jamaneurol.2017.3475
Hayakawa K, Chan SJ, Mandeville ET, Park JH, Bruzzese M, Montaner J, Arai K, Rosell A, Lo E (2018) Protective effects of endothelial progenitor cell-derived extracellular mitochondria in brain endothelium. Stem Cells 36:1404–1410. https://doi.org/10.1002/stem.2856
Herst PM, Dawson RH, Berridge MV (2018) Intercellular communication in tumour biology: a role for mitochondrial transfer. Front Oncol 8:344. https://doi.org/10.3389/fonc.2018.00344
Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J (2012) Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18:759–765. https://doi.org/10.1038/nm.2736
Kaza AK, Wamala I, Friehs I, Kuebler JD, Rathod RH, Berra I, Ericsson M, Yao R, Thedsanamoorthy JK, Zurakowski D, Levitsky S, Del Nido PJ, Cowan DB, McCully JD (2017) Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion. J Thorac Cardiovasc Surg 153:934–943. https://doi.org/10.1016/j.jtcvs.2016.10.077
King MP, Attardi G (1988) Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52:811–819. https://doi.org/10.1016/0092-8674(88)90423-0
Kiriyama Y, Nochi H (2018) Intra- and intercellular quality control mechanisms of mitochondria. Cells 7(1):1. https://doi.org/10.3390/cells7010001
Kitani T, Kami D, Matoba S, Gojo S (2014) Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med 18:1694–1703. https://doi.org/10.1111/jcmm.12316
Kumar SR (2017) Mitochondrial transplantation: Another miracle of molecular medicine? J Thorac Cardiovasc Surg 154:284–285. https://doi.org/10.1016/j.jtcvs.2017.03.074
Kuo CC, Su HL, Chang TL, Chiang CY, Sheu ML, Cheng FC, Chen CJ, Sheehan J, Pan HC (2017) Prevention of axonal degeneration by perineurium injection of mitochondria in a sciatic nerve crush injury model. Neurosurgery 80:475–488. https://doi.org/10.1093/neuros/nyw090
Marcoux G, Magron A, Sut C, Laroche A, Laradi S, Hamzeh-Cognasse H, Allaeys I, Cabon O, Julien AS, Garraud O, Cognasse F, Boilard E (2019) Platelet-derived extracellular vesicles convey mitochondrial DAMPs in platelet concentrates and their levels are associated with adverse reactions. Transfusion 59:2403–2414. https://doi.org/10.1111/trf.15300
Miliotis S, Nicolalde B, Ortega M, Yepez J, Caicedo A (2019) Forms of extracellular mitochondria and their impact in health. Mitochondrion 48:16–30. https://doi.org/10.1016/j.mito.2019.02.002
Murray LMA, Krasnodembskaya AD (2019) Concise review: Intercellular communication via organelle transfer in the biology and therapeutic applications of stem cells. Stem Cells 37:14–25. https://www.StemCells.com
Nakamura Y, Park JH, Hayakawa K (2020) Therapeutic use of extracellular mitochondria in CNS injury and disease. Exp Neurol 324:113114. https://doi.org/10.1016/j.expneurol.2019.113114
Pacak CA, Preble JM, Kondo H, Seibel P, Levitsky S, del Nido PJ, Cowan DB, McCully JD (2015) Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function. Biol Open 4:622. https://doi.org/10.1242/bio.201511478
Paliwal S, Chaudhuri R, Agrawal A, Mohanty S (2018) Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci 25:31. https://doi.org/10.1186/s12929-018-0429-1
Pepe S (2017) Mitochondria “muscle in” as a potential adjunct therapy in cardiothoracic surgery. J Thor Cardiovasc Surgery 153:944–946. https://doi.org/10.1016/j.jtcvs.2016.11.046
Puhm F, Afonyushkin T, Resch U, Obermayer G, Rohde M, Penz T, Schuster M, Wagner G, Rendeiro AF, Melki I, Kaun C, Wojta J, Bock C, Jilma B, Mackman N, Boilard E, Binder CJ (2019) Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells. Circ Res 125:43–52. https://doi.org/10.1161/CIRCRESAHA.118.314601
Robicsek O, Ene HM, Karry R, Ytzhaki O, Asor E, McPhie D, Cohen BM, Ben-Yehuda R, Weiner I, Ben-Shachar D (2018) Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophr Bull 44(2):432–442. https://doi.org/10.1093/schbul/sbx077
Rodriguez AM, Nakhle J, Griessinger E, Vignais ML (2018) Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle 17:712–721. https://doi.org/10.1080/15384101.2018.1445906
Roushandeh AM, Kuwahara Y, Roudkenar MH (2019) Mitochondrial transplantation as a potential and novel master key for treatment of various incurable diseases. Cytotechnology 71:647–663. https://doi.org/10.1007/s10616-019-00302-9
Sedlackova L, Korolchuk VI (2019) Mitochondrial quality control as a key determinant of cell survival. Biochim Biophys Acta Mol Cell Res 1866:575–587. https://doi.org/10.1016/j.bbamcr.2018
Shi X, Zhao M, Fu C, 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
Shin B, Cowan DB, Emani SM, Del Nido PJ, McCully JD (2017) Mitochondrial transplantation in myocardial ischemia and reperfusion injury. Adv Exp Med Biol 982:595–619. https://doi.org/10.1007/978-3-319-55330-6_31
Singh B, Modica-Napolitano JS, Singh KK (2017) Defining the Momiome: promiscuous information transfer by mobile mitochondria and mitochondrial genome. Semin Cancer Biol 47:1–17. https://doi.org/10.1016/j.semcancer.2017.05.004
Sun C, Liu X, Wang B, Wang Z, Liu Y, Di C, Si J, Li H, Wu Q, Xu D, Li J, Li G, Wang Y, Wang F, Zhang H (2019) Endocytosis-mediated mitochondrial transplantation: transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity. Theranostics 9(12):3595–3607. https://doi.org/10.7150/thno.33100.eCollection2019
Wang J, Li H, Yao Y, Zhao T, Chen YY, Shen YL, Wang LL, Zhu Y (2018) Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury. Stem Cell Res Ther 9:106. https://doi.org/10.1186/s13287-018-0832-2
Zhao Z, Zhou Y, Hilton T, Li F, Han C, Liu L, Yuan H, Li Y, Xu X, Wu X, Zhang F, Thiagarajan P, Cap A, Shi FD, Zhang J, Dong JF (2020) Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity. Haematologica 105:209–217. https://doi.org/10.3324/haematol.2018.214932
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Popov, LD. One step forward: extracellular mitochondria transplantation. Cell Tissue Res 384, 607–612 (2021). https://doi.org/10.1007/s00441-021-03428-5
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DOI: https://doi.org/10.1007/s00441-021-03428-5