Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases: mechanisms, prospective, and challenges

Abstract

Mitochondrial transplantation (MT) is a promising therapeutic strategy that involves introducing healthy mitochondria into damaged tissues to restore cellular function. This approach has shown promise in treating cardiac diseases, such as ischemia-reperfusion injury, myocardial infarction, and heart failure, where mitochondrial dysfunction plays a crucial role. Transplanting healthy mitochondria into affected cardiac tissue has resulted in improved cardiac function, reduced infract size, and enhanced cell survival in preclinical studies. Beyond cardiac applications, MT is also being explored for its potential to address various noncardiac diseases, including stroke, infertility, and genetic mitochondrial disorders. Ongoing research focused on refining techniques for mitochondrial isolation, preservation, and targeted delivery is bolstering the prospects of MT as a clinical therapy. As the scientific community gains a deeper understanding of mitochondrial dynamics and pathology, the development of MT as a clinical therapy holds significant promise. This review provides an overview of recent research on MT and discusses the methodologies involved, including sources, isolation, delivery, internalization, and distribution of mitochondria. Additionally, it explores the effects of MT and potential mechanisms in cardiac diseases, as well as non-cardiac diseases. Future prospects for MT are also discussed.

Keywords

mitochondria / mitochondrial transplantation / heart / cardiac diseases / noncardiac diseases

References

[1] Friedman JR , Nunnari J . Mitochondrial form and function. Nature 2014; 505: 335- 43.

[2] McBride HM , Neuspiel M , Wasiak S . Mitochondria: more than just a powerhouse. Curr Biol 2006; 16: R551- 60.

[3] Amorim JA , Coppotelli G , Rolo AP , et al. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022; 18: 243- 58.

[4] Nunnari J , Suomalainen A . Mitochondria: in sickness and in health. Cell 2012; 148: 1145- 59.

[5] Meerson FZ , Zaletayeva TA , Lagutchev SS , et al. Structure and mass of mitochondria in the process of compensatory hyperfunction and hypertrophy of the heart. Exp Cell Res 1964; 36: 568- 78.

[6] Ramachandra CJA , Hernandez-Resendiz S , Crespo-Avilan GE , et al. Mitochondria in acute myocardial infarction and cardioprotection. EBioMedicine 2020; 57: 102884.

[7] McCully JD , Levitsky S , Del Nido PJ , et al. Mitochondrial transplantation for therapeutic use. Clinical and Translational Medicine 2016; 5: 16.

[8] Davidson SM , Ferdinandy P , Andreadou I , et al; CARDIOPROTECTION COST Action (CA16225) . Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol 2019; 73: 89- 99.

[9] Ptaszek LM , Mansour M , Ruskin JN , et al. Towards regenerative therapy for cardiac disease. Lancet 2012; 379: 933- 42.

[10] van Berlo JH , Kanisicak O , Maillet M , et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014; 509: 337- 41.

[11] Vagnozzi RJ , Maillet M , Sargent MA , et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature 2020; 577: 405- 9.

[12] Sanganalmath SK , Bolli R . Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013; 113: 810- 34.

[13] Nguyen PK , Rhee J-W , Wu JC . Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review. JAMA Cardiol 2016; 1: 831- 41.

[14] Islam MN , Das SR , Emin MT , et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18: 759- 65.

[15] Cselenyák A , Pankotai E , Horváth EM , et al. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol 2010; 11: 29.

[16] McCully JD , Cowan DB , Pacak CA , et al. Injection of isolated mitochondria during early reperfusion for cardioprotection. Am J Physiol Heart Circ Physiol 2009; 296: H94- H105.

[17] Emani SM , Piekarski BL , Harrild D , et al. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2017; 154: 286- 9.

[18] Moskowitzova K , Orfany A , Liu K , et al. Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 2020; 318: L78- 88.

[19] Lin H-C , Liu S-Y , Lai H-S , et al. Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats. Shock 2013; 39: 304- 10.

[20] Fu A , Shi X , Zhang H , et al. Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front Pharmacol 2017; 8: 241.

[21] Zhang Z , Ma Z , Yan C , et al. Muscle-derived autologous mitochondrial transplantation: a novel strategy for treating cerebral ischemic injury. Behav Brain Res 2019; 356: 322- 31.

[22] Pourmohammadi-Bejarpasi Z , Roushandeh AM , Saberi A , et al. Mesenchymal stem cells-derived mitochondria transplantation mitigates I/R-induced injury, abolishes I/R-induced apoptosis, and restores motor function in acute ischemia stroke rat model. Brain Res Bull 2020; 165: 70- 80.

[23] Yan C , Ma Z , Ma H , et al. Mitochondrial transplantation attenuates brain dysfunction in sepsis by driving microglial M2 polarization. Mol Neurobiol 2020; 57: 3875- 90.

[24] Nakamura Y , Lo EH , Hayakawa K . Placental mitochondria therapy for cerebral ischemia-reperfusion injury in mice. Stroke 2020; 51: 3142- 6.

[25] Huang P-J , Kuo C-C , Lee H-C , et al. Transferring xenogenic mitochondria provides neural protection against ischemic stress in ischemic rat brains. Cell Transplant 2016; 25: 913- 27.

[26] Zhang B , Gao Y , Li Q , et al. Effects of brain-derived mitochondria on the function of neuron and vascular endothelial cell after traumatic brain injury. World Neurosurgery 2020; 138: e1- 9.

[27] Orfany A , Arriola CG , Doulamis IP , et al. Mitochondrial transplantation ameliorates acute limb ischemia. J Vasc Surg 2020; 71: 1014- 26.

[28] Doulamis IP , Guariento A , Duignan T , et al. Mitochondrial transplantation by intra-arterial injection for acute kidney injury. Am J Physiol Renal Physiol 2020; 319: F403- 13.

[29] Lesnefsky EJ , Chen Q , Tandler B , et al. Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies. Annu Rev Pharmacol Toxicol 2017; 57: 535- 65.

[30] Kalogeris T , Baines CP , Krenz M , et al. Ischemia/reperfusion. Comprehensive Physiology 2016; 7: 113- 70.

[31] Su X , Zhou M , Li Y , et al. Protective effects of natural products against myocardial ischemia/reperfusion: mitochondria-targeted therapeutics. Biomed Pharmacother 2022; 149: 112893.

[32] Cowan DB , Yao R , Thedsanamoorthy JK , et al. Transit and integration of extracellular mitochondria in human heart cells. Sci Rep 2017; 7: 17450.

[33] Ma H , Jiang T , Tang W , et al. Transplantation of platelet-derived mitochondria alleviates cognitive impairment and mitochondrial dysfunction in db/db mice. Clin Sci 2020; 134: 2161- 75.

[34] Sun C-K , Lee F-Y , Kao Y-H , et al. Systemic combined melatonin-mitochondria treatment improves acute respiratory distress syndrome in the rat. J Pineal Res 2015; 58: 137- 50.

[35] Masuzawa A , Black KM , Pacak CA , et al. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2013; 304: H966- 82.

[36] Shin B , Saeed MY , Esch JJ , et al. A novel biological strategy for myocardial protection by intracoronary delivery of mitochondria: safety and efficacy. JACC Basic Transl Sci 2019; 4: 871- 88.

[37] Weixler V , Lapusca R , Grangl G , et al. Autogenous mitochondria transplantation for treatment of right heart failure. J Thorac Cardiovasc Surg 2021; 162: e111- 21.

[38] Nicholas Borcherding WJ . Giwa R, Kory L. Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood. Cell Metab 2022; 34: 1499- 513.

[39] Shin B , Cowan DB , Emani SM , et al. Mitochondrial transplantation in myocardial ischemia and reperfusion injury. Adv Exp Med Biol 2017; 982: 595- 619.

[40] Xie Q , Zeng J , Zheng Y , et al. Mitochondrial transplantation attenuates cerebral ischemia-reperfusion injury: possible involvement of mitochondrial component separation. Oxid Med Cell Longevity 2021; 2021: 1006636.

[41] Ali Pour P , Kenney MC , Kheradvar A . Bioenergetics consequences of mitochondrial transplantation in cardiomyocytes. J Am Heart Associat 2020; 9: e014501.

[42] Preble JM , Sidney Levitsky HK , McCully JD . Quality control parameters for mitochondria transplant in cardiac tissue. JSM Biochem Molec Biol 2014; 2: 1008.

[43] Claude A . Fractionation of mammalian liver cells by differential centrifugation: II. Experimental procedures and results. J Exp Med 1946; 84: 61- 89.

[44] Sims NR . Rapid isolation of metabolically active mitochondria from rat brain and subregions using Percoll density gradient centrifugation. J Neurochem 1990; 55: 698- 707.

[45] Hornig-Do H-T , Günther G , Bust M , et al. Isolation of functional pure mitochondria by superparamagnetic microbeads. Anal Biochem 2009; 389: 1- 5.

[46] Preble JM , Pacak CA , Kondo H , et al. Rapid isolation and purification of mitochondria for transplantation by tissue dissociation and differential filtration. J Visualized Exper 1682; 2014: e5.

[47] Clark MA , Shay JW . Mitochondrial transformation of mammalian cells. Nature 1982; 295: 605- 7.

[48] Pinkert CA , Irwin MH , Johnson LW , et al. Mitochondria transfer into mouse ova by microinjection. Transgenic Res 1997; 6: 379- 83.

[49] Kim MJ , Hwang JW , Yun C-K , et al. Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep 2018; 8: 3330.

[50] Chang J-C , Liu K-H , Chuang C-S , et al. Treatment of human cells derived from MERRF syndrome by peptide-mediated mitochondrial delivery. Cytotherapy 2013; 15: 1580- 96.

[51] Wu S , Zhang A , Li S , et al. Polymer functionalization of isolated mitochondria for cellular transplantation and metabolic phenotype alteration. Adv Sci 2018; 5: 1700530.

[52] Macheiner T , Fengler VHI , Agreiter M , et al. Magnetomitotransfer: an efficient way for direct mitochondria transfer into cultured human cells. Sci Rep 2016; 6: 35571.

[53] Wu T-H , Sagullo E , Case D , et al. Mitochondrial transfer by photothermal nanoblade restores metabolite profile in mammalian cells. Cell Metab 2016; 23: 921- 9.

[54] Kaza AK , Wamala I , Friehs I , et al. Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/ reperfusion. J Thorac Cardiovasc Surg 2017; 153: 934- 43.

[55] Cowan DB , Yao R , Akurathi V , et al. Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 2016; 11: e0160889.

[56] Kesner EE , Saada-Reich A , Lorberboum-Galski H . Characteristics of mitochondrial transformation into human cells. Sci Rep 2016; 6: 26057.

[57] Brestoff JR , Wilen CB , Moley JR , et al. Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab 2021; 33: 270- 82.e8.

[58] Katrangi E , D'Souza G , Boddapati SV , et al. Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res 2007; 10: 561- 70.

[59] Pacak CA , Preble JM , Kondo H , et al. Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function. Biology Open 2015; 4: 622- 6.

[60] Kitani T , Kami D , Matoba S , et al. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med 2014; 18: 1694- 703.

[61] Patel D , Rorbach J , Downes K , et al. Macropinocytic entry of isolated mitochondria in epidermal growth factor-activated human osteosarcoma cells. Sci Rep 2017; 7: 12886.

[62] Lou E , Fujisawa S , Morozov A , et al. Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS One 2012; 7: e33093.

[63] Hayakawa K , Esposito E , Wang X , et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 2016; 535: 551- 5.

[64] Sun X , Gao R , Li W , et al. Alda-1 treatment promotes the therapeutic effect of mitochondrial transplantation for myocardial ischemia-reperfusion injury. Bioact Mater 2021; 6: 2058- 69.

[65] Guariento A , Doulamis IP , Duignan T , et al. Mitochondrial transplantation for myocardial protection in ex-situ-perfused hearts donated after circulatory death. J Heart Lung Transpl 2020; 39: 1279- 88.

[66] Guariento A , Blitzer D , Doulamis I , et al. Preischemic autologous mitochondrial transplantation by intracoronary injection for myocardial protection. J Thorac Cardiovasc Surg 2020; 160: e15- 29.

[67] Blitzer D , Guariento A , Doulamis IP , et al. Delayed transplantation of autologous mitochondria for cardioprotection in a porcine model. Ann Thorac Surg 2020; 109: 711- 9.

[68] Guariento A , Piekarski BL , Doulamis IP , et al. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2021; 162: 992- 1001.

[69] Doulamis IP , Guariento A , Duignan T , et al. Mitochondrial transplantation for myocardial protection in diabetic hearts. Eur J CardioThoracic Surg 2020; 57: 836- 45.

[70] Chang J-C , Wu S-L , Liu K-H , et al. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res 2016; 170: 40- 56.e3.

[71] Robicsek O , Ene HM , Karry R , et al. 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 2018; 44: 432- 42.

[72] Zhang Z , Yan C , Miao J , et al. Muscle-derived mitochondrial transplantation reduces inflammation, enhances bacterial clearance, and improves survival in sepsis. Shock 2021; 56: 108- 18.

[73] Jabbari H , Roushandeh AM , Rostami MK , et al. Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat. Biochim Biophys Acta Mol Basis Dis 2020; 1866: 165809.

[74] Wolf DP , Mitalipov N , Mitalipov S . Mitochondrial replacement therapy in reproductive medicine. Trends Mol Med 2015; 21: 68- 76.

[75] Cohen J , Scott R , Alikani M , et al. Ooplasmic transfer in mature human oocytes. Mol Hum Reprod 1998; 4: 269- 80.

[76] Oktay K , Baltaci V , Sonmezer M , et al. Oogonial precursor cell-derived autologous mitochondria injection to improve outcomes in women with multiple IVF failures due to low oocyte quality: a clinical translation. Reprod Sci 2015; 22: 1612- 7.

[77] Ko S-F , Chen Y-L , Sung P-H , et al. Hepatic 31 P-magnetic resonance spectroscopy identified the impact of melatonin-pretreated mitochondria in acute liver ischaemia-reperfusion injury. J Cell Mol Med 2020; 24: 10088- 99.

[78] Labarta E , de Los Santos MJ , Herraiz S , et al. Autologous mitochondrial transfer as a complementary technique to intracytoplasmic sperm injection to improve embryo quality in patients undergoing in vitro fertilization-a randomized pilot study.Fertil Steril 2019; 111: 86- 96.

[79] Moskowitzova K , Shin B , Liu K , et al. Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation. J Heart Lung Transpl 2019; 38: 92- 9.

[80] Zhang A , Liu Y , Pan J , et al. Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance. Molec Therapy: J Am Soc Gene Therapy 2023; 31: 1468- 79.

[81] Hwang JW , Lee MJ , Chung TN , et al. The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat. Crit Care 2021; 25: 20.

[82] Ma H , Marti Gutierrez N , Morey R , et al. Incompatibility between nuclear and mitochondrial genomes contributes to an interspecies reproductive barrier. Cell Metab 2016; 24: 283- 94.

[83] Meiklejohn CD , Holmbeck MA , Siddiq MA , et al. An incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila. PLoS Genet 2013; 9: e1003238.

[84] Wei W , Schon KR , Elgar G , et al. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature 2022; 611: 105- 14.

[85] McCully JD , Cowan DB , Emani SM , et al. Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion 2017; 34: 127- 34.

[86] Bertero E , O’Rourke B , Maack C . Mitochondria do not survive calcium overload during transplantation. Circ Res 2020; 126: 784- 6.

[87] Marchi S , Guilbaud E , Tait SWG , et al. Mitochondrial control of inflammation. Nat Rev Immunol 2023; 23: 159- 73.

[88] Lin L , Xu H , Bishawi M , et al. Circulating mitochondria in organ donors promote allograft rejection. Am J Transpl 2019; 19: 1917- 29.

[89] Puhm F , Afonyushkin T , Resch U , et al. Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce Type I IFN and TNF responses in endothelial cells. Circ Res 2019; 125: 43- 52.

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