Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Mitotherapy as a Novel Therapeutic Strategy for Mitochondrial Diseases

Author(s): Ailing Fu*

Volume 13, Issue 1, 2020

Page: [41 - 49] Pages: 9

DOI: 10.2174/1874467212666190920144115

Price: $65

Abstract

Background: The mitochondrion is a multi-functional organelle that is mainly responsible for energy supply in the mammalian cells. Over 100 human diseases are attributed to mitochondrial dysfunction. Mitochondrial therapy (mitotherapy) aims to transfer functional exogenous mitochondria into mitochondria-defective cells for recovery of the cell viability and consequently, prevention of the disease progress.

Objective: The review summarizes the evidence on exogenous mitochondria that can directly enter mammalian cells for disease therapy following local and intravenous administration, and suggests that when healthy cells donate their mitochondria to damaged cells, the mitochondrial transfer between cells serve as a new mode of cell rescue. Then the transferred mitochondria play their roles in recipient cells, including energy production and maintenance of cell function.

Conclusion: Mitotherapy makes the of modulation of cell survival possible, and it would be a potential therapeutic strategy for mitochondrial diseases.

Keywords: Mitotherapy, mitochondrial transplantation, cell-to-cell communication, mitochondrial diseases, ROS, cell apoptosis.

Graphical Abstract
[1]
Friedman, J.R.; Nunnari, J. Mitochondrial form and function. Nature, 2014, 505(7483), 335-343.
[http://dx.doi.org/10.1038/nature12985] [PMID: 24429632]
[2]
Zinovkin, R.A.; Zamyatnin, A.A. Mitochondria-targeted drugs. Curr. Mol. Pharmacol., 2019, 12(3), 202-214.
[http://dx.doi.org/10.2174/1874467212666181127151059] [PMID: 30479224]
[3]
Parikh, S.; Goldstein, A.; Koenig, M.K.; Scaglia, F.; Enns, G.M.; Saneto, R.; Anselm, I.; Cohen, B.H.; Falk, M.J.; Greene, C.; Gropman, A.L.; Haas, R.; Hirano, M.; Morgan, P.; Sims, K.; Tarnopolsky, M.; Van Hove, J.L.; Wolfe, L.; DiMauro, S. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet. Med., 2015, 17(9), 689-701.
[http://dx.doi.org/10.1038/gim.2014.177] [PMID: 25503498]
[4]
Suomalainen, A.; Battersby, B.J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol., 2018, 19(2), 77-92.
[http://dx.doi.org/10.1038/nrm.2017.66] [PMID: 28792006]
[5]
Lightowlers, R.N.; Taylor, R.W.; Turnbull, D.M. Mutations causing mitochondrial disease: What is new and what challenges remain? Science, 2015, 349(6255), 1494-1499.
[http://dx.doi.org/10.1126/science.aac7516] [PMID: 26404827]
[6]
Paine, A.; Jaiswal, M.K. Promise and pitfalls of mitochondrial replacement for prevention and cure of heritable neurodegenerative diseases caused by deleterious mutations in mitochondrial DNA. Front. Cell. Neurosci., 2016, 10, 219.
[http://dx.doi.org/10.3389/fncel.2016.00219] [PMID: 27721743]
[7]
Cherry, C.; Thompson, B.; Saptarshi, N.; Wu, J.; Hoh, J. 2016: A mitochondria’ odyssey. Trends Mol. Med., 2016, 22(5), 391-403.
[http://dx.doi.org/10.1016/j.molmed.2016.03.009] [PMID: 27151392]
[8]
Hirano, M.; Emmanuele, V.; Quinzii, C.M. Emerging therapies for mitochondrial diseases. Essays Biochem., 2018, 62(3), 467-481.
[http://dx.doi.org/10.1042/EBC20170114] [PMID: 29980632]
[9]
Amini, P.; Mirtavoos-Mahyari, H.; Motevaseli, E.; Shabeeb, D.; Musa, A.E.; Cheki, M.; Farhood, B.; Yahyapour, R.; Shirazi, A.; Goushbolagh, N.A.; Najafi, M. Mechanisms for radioprotection by melatonin; can it be used as a radiation countermeasure? Curr. Mol. Pharmacol., 2019, 12(1), 2-11.
[10]
Chinnery, P.F. Mitochondrial disease in adults: what’s old and what’s new? EMBO Mol. Med., 2015, 7(12), 1503-1512.
[http://dx.doi.org/10.15252/emmm.201505079] [PMID: 26612854]
[11]
Vafai, S.B.; Mootha, V.K. Mitochondrial disorders as windows into an ancient organelle. Nature, 2012, 491(7424), 374-383.
[http://dx.doi.org/10.1038/nature11707] [PMID: 23151580]
[12]
Shitara, H.; Kaneda, H.; Sato, A.; Inoue, K.; Ogura, A.; Yonekawa, H.; Hayashi, J.I. Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from liver cells, occurs throughout embryogenesis. Genetics, 2000, 156(3), 1277-1284.
[PMID: 11063701]
[13]
Herbert, M.; Turnbull, D. Progress in mitochondrial replacement therapies. Nat. Rev. Mol. Cell Biol., 2018, 19(2), 71-72.
[http://dx.doi.org/10.1038/nrm.2018.3] [PMID: 29358685]
[14]
Clark, M.A.; Shay, J.W. Mitochondrial transformation of mammalian cells. Nature, 1982, 295(5850), 605-607.
[http://dx.doi.org/10.1038/295605a0] [PMID: 7057918]
[15]
Katrangi, E.; D’Souza, G.; Boddapati, S.V.; Kulawiec, M.; Singh, K.K.; Bigger, B.; Weissig, V. Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res., 2007, 10(4), 561-570.
[http://dx.doi.org/10.1089/rej.2007.0575] [PMID: 18069915]
[16]
Kitani, T.; Kami, D.; Kawasaki, T.; Nakata, M.; Matoba, S.; Gojo, S. Direct human mitochondrial transfer: a novel concept based on the endosymbiotic theory. Transplant. Proc., 2014, 46(4), 1233-1236.
[http://dx.doi.org/10.1016/j.transproceed.2013.11.133] [PMID: 24815168]
[17]
Kesner, E.E.; Saada-Reich, A.; Lorberboum-Galski, H. Characteristics of mitochondrial transformation into human cells. Sci. Rep., 2016, 6, 26057.
[http://dx.doi.org/10.1038/srep26057] [PMID: 27184109]
[18]
Hayakawa, K.; Esposito, E.; Wang, X.; Terasaki, Y.; Liu, Y.; Xing, C.; Ji, X.; Lo, E.H. Transfer of mitochondria from astrocytes to neurons after stroke. Nature, 2016, 535(7613), 551-555.
[http://dx.doi.org/10.1038/nature18928] [PMID: 27466127]
[19]
Hessvik, N.P.; Llorente, A. Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci., 2018, 75(2), 193-208.
[http://dx.doi.org/10.1007/s00018-017-2595-9] [PMID: 28733901]
[20]
Plotnikov, E.Y.; Babenko, V.A.; Silachev, D.N.; Zorova, L.D.; Khryapenkova, T.G.; Savchenko, E.S.; Pevzner, I.B.; Zorov, D.B. Intercellular Transfer of Mitochondria. Biochemistry (Mosc.), 2015, 80(5), 542-548.
[http://dx.doi.org/10.1134/S0006297915050041] [PMID: 26071771]
[21]
Wang, X.; Gerdes, H.H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ., 2015, 22(7), 1181-1191.
[http://dx.doi.org/10.1038/cdd.2014.211] [PMID: 25571977]
[22]
Zhang, Y.; Yu, Z.; Jiang, D.; Liang, X.; Liao, S.; Zhang, Z.; Yue, W.; Li, X.; Chiu, S.M.; Chai, Y.H.; Liang, Y.; Chow, Y.; Han, S.; Xu, A.; Tse, H.F.; Lian, Q. iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-α yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem Cell Reports, 2016, 7(4), 749-763.
[http://dx.doi.org/10.1016/j.stemcr.2016.08.009] [PMID: 27641650]
[23]
Cowan, D.B.; Yao, R.; Akurathi, V.; Snay, E.R.; Thedsanamoorthy, J.K.; Zurakowski, D.; Ericsson, M.; Friehs, I.; Wu, Y.; Levitsky, S.; Del Nido, P.J.; Packard, A.B.; McCully, J.D. Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One, 2016, 11(8)e0160889
[http://dx.doi.org/10.1371/journal.pone.0160889] [PMID: 27500955]
[24]
Fu, A.; Shi, X.; Zhang, H.; Fu, B. Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front. Pharmacol., 2017, 8, 241.
[http://dx.doi.org/10.3389/fphar.2017.00241] [PMID: 28536524]
[25]
Shi, X.; Zhao, M.; Fu, C.; Fu, A. Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion, 2017, 34, 91-100.
[http://dx.doi.org/10.1016/j.mito.2017.02.005] [PMID: 28242362]
[26]
Chien, L.; Liang, M.Z.; Chang, C.Y.; Wang, C.; Chen, L. Mitochondrial therapy promotes regeneration of injured hippocampal neurons. Biochim. Biophys. Acta Mol. Basis Dis., 2018, 1864(9 Pt B), 3001-3012.
[http://dx.doi.org/10.1016/j.bbadis.2018.06.012] [PMID: 29913215]
[27]
Scholpa, N.E.; Schnellmann, R.G. Mitochondrial-based therapeutics for the treatment of spinal cord injury: mitochondrial biogenesis as a potential pharmacological target. J. Pharmacol. Exp. Ther., 2017, 363(3), 303-313.
[http://dx.doi.org/10.1124/jpet.117.244806] [PMID: 28935700]
[28]
Zhang, Z.; Ma, Z.; Yan, C.; Pu, K.; Wu, M.; Bai, J.; Li, Y.; Wang, Q. Muscle-derived autologous mitochondrial transplantation: A novel strategy for treating cerebral ischemic injury. Behav. Brain Res., 2019, 356, 322-331.
[http://dx.doi.org/10.1016/j.bbr.2018.09.005] [PMID: 30213662]
[29]
Robicsek, O.; Ene, H.M.; Karry, R.; Ytzhaki, O.; Asor, E.; McPhie, D.; Cohen, B.M.; Ben-Yehuda, R.; Weiner, I.; Ben-Shachar, D. 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(2), 432-442.
[http://dx.doi.org/10.1093/schbul/sbx077] [PMID: 28586483]
[30]
Gollihue, J.L.; Patel, S.P.; Eldahan, K.C.; Cox, D.H.; Donahue, R.R.; Taylor, B.K.; Sullivan, P.G.; Rabchevsky, A.G. Effects of Mitochondrial Transplantation on Bioenergetics, Cellular Incorporation, and Functional Recovery after Spinal Cord Injury. J. Neurotrauma, 2018, 35(15), 1800-1818.
[http://dx.doi.org/10.1089/neu.2017.5605] [PMID: 29648982]
[31]
Masuzawa, A.; Black, K.M.; Pacak, C.A.; Ericsson, M.; Barnett, R.J.; Drumm, C.; Seth, P.; Bloch, D.B.; Levitsky, S.; Cowan, D.B.; McCully, J.D. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol., 2013, 304(7), H966-H982.
[http://dx.doi.org/10.1152/ajpheart.00883.2012] [PMID: 23355340]
[32]
Bertero, E.; Maack, C.; O’Rourke, B. Mitochondrial transplantation in humans: “magical” cure or cause for concern? J. Clin. Invest., 2018, 128(12), 5191-5194.
[http://dx.doi.org/10.1172/JCI124944] [PMID: 30371508]
[33]
Jiang, X.P.; Elliott, R.L.; Head, J.F. Exogenous normal mammary epithelial mitochondria suppress glycolytic metabolism and glucose uptake of human breast cancer cells. Breast Cancer Res. Treat., 2015, 153(3), 519-529.
[http://dx.doi.org/10.1007/s10549-015-3583-0] [PMID: 26407856]
[34]
Wang, Q.H.; Fu, C.; Li, X.R.; Hou, Y.X.; Fu, A. Mechanism of melanoma growth inhibition by exogenous Mitochondria. Yao Xue Xue Bao, 2019, 54(3), 463-468.
[35]
Kaipparettu, B.A.; Ma, Y.; Park, J.H.; Lee, T.L.; Zhang, Y.; Yotnda, P.; Creighton, C.J.; Chan, W.Y.; Wong, L.J. Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways. PLoS One, 2013, 8(5)e61747
[http://dx.doi.org/10.1371/journal.pone.0061747] [PMID: 23671572]
[36]
Shi, X.; Bai, H.; Zhao, M.; Li, X.; Sun, X.; Jiang, H.; Fu, A. Treatment of acetaminophen-induced liver injury with exogenous mitochondria in mice. Transl. Res., 2018, 196, 31-41.
[http://dx.doi.org/10.1016/j.trsl.2018.02.003] [PMID: 29548626]
[37]
Zhu, L.; Zhang, J.; Zhou, J.; Lu, Y.; Huang, S.; Xiao, R.; Yu, X.; Zeng, X.; Liu, B.; Liu, F.; Sun, M.; Dai, M.; Hao, Q.; Li, J.; Wang, T.; Li, T.; Hu, Q. Mitochondrial transplantation attenuates hypoxic pulmonary hypertension. Oncotarget, 2016, 7(31), 48925-48940.
[http://dx.doi.org/10.18632/oncotarget.10596] [PMID: 27419637]
[38]
Kitani, T.; Kami, D.; Matoba, S.; Gojo, S. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J. Cell. Mol. Med., 2014, 18(8), 1694-1703.
[http://dx.doi.org/10.1111/jcmm.12316] [PMID: 24912369]
[39]
Pacak, C.A.; Preble, J.M.; Kondo, H.; Seibel, P.; Levitsky, S.; Del Nido, P.J.; Cowan, D.B.; McCully, J.D. Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function. Biol. Open, 2015, 4(5), 622-626.
[http://dx.doi.org/10.1242/bio.201511478] [PMID: 25862247]
[40]
Tuma, P.; Hubbard, A.L. Transcytosis: crossing cellular barriers. Physiol. Rev., 2003, 83(3), 871-932.
[http://dx.doi.org/10.1152/physrev.00001.2003] [PMID: 12843411]
[41]
Chen, X.; Li, J.; Hou, J.; Xie, Z.; Yang, F. Mammalian mitochondrial proteomics: insights into mitochondrial functions and mitochondria-related diseases. Expert Rev. Proteomics, 2010, 7(3), 333-345.
[http://dx.doi.org/10.1586/epr.10.22] [PMID: 20536306]
[42]
Koren, E.; Torchilin, V.P. Drug carriers for vascular drug delivery. IUBMB Life, 2011, 63(8), 586-595.
[http://dx.doi.org/10.1002/iub.496] [PMID: 21766415]
[43]
Kuo, Y.C.; Chung, C.Y. Transcytosis of CRM197-grafted polybutylcyanoacrylate nanoparticles for delivering zidovudine across human brain-microvascular endothelial cells. Colloids Surf. B Biointerfaces, 2012, 91, 242-249.
[http://dx.doi.org/10.1016/j.colsurfb.2011.11.007] [PMID: 22137614]
[44]
Simionescu, M.; Popov, D.; Sima, A. Endothelial transcytosis in health and disease. Cell Tissue Res., 2009, 335(1), 27-40.
[http://dx.doi.org/10.1007/s00441-008-0688-3] [PMID: 18836747]
[45]
Leung, P.S.; Rossaro, L.; Davis, P.A.; Park, O.; Tanaka, A.; Kikuchi, K.; Miyakawa, H.; Norman, G.L.; Lee, W.; Gershwin, M.E. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology, 2007, 46(5), 1436-1442.
[http://dx.doi.org/10.1002/hep.21828] [PMID: 17657817]
[46]
Abdelmegeed, M.A.; Ha, S.K.; Choi, Y.; Akbar, M.; Song, B.J. Role of CYP2E1 in mitochondrial dysfunction and hepatic injury by alcohol and non-alcoholic substances. Curr. Mol. Pharmacol., 2017, 10(3), 207-225.
[http://dx.doi.org/10.2174/1874467208666150817111114] [PMID: 26278393]
[47]
Lin, L.; Xu, H.; Bishawi, M.; Feng, F.; Samy, K.; Truskey, G.; Barbas, A.S.; Kirk, A.D.; Brennan, T.V. Circulating mitochondria in organ donors promote allograft rejection. Am. J. Transplant., 2019, 19(7), 1917-1929.
[http://dx.doi.org/10.1111/ajt.15309] [PMID: 30761731]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy