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Letter by McCully et al Regarding Article, “Mitochondria Do Not Survive Calcium Overload"

2020; Lippincott Williams & Wilkins; Volume: 126; Issue: 8 Linguagem: Inglês

10.1161/circresaha.120.316832

1524-4571

James D. McCully, Sitaram M. Emani, Pedro J. del Nido,

Cardiac Ischemia and Reperfusion

HomeCirculation ResearchVol. 126, No. 8Letter by McCully et al Regarding Article, "Mitochondria Do Not Survive Calcium Overload" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by McCully et al Regarding Article, "Mitochondria Do Not Survive Calcium Overload" James D. McCully, Sitaram M. Emani and Pedro J. del Nido James D. McCullyJames D. McCully From the Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, MA. , Sitaram M. EmaniSitaram M. Emani https://orcid.org/0000-0002-6048-2078 From the Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, MA. and Pedro J. del NidoPedro J. del Nido From the Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, MA. Originally published9 Apr 2020https://doi.org/10.1161/CIRCRESAHA.120.316832Circulation Research. 2020;126:e56–e57In Response:The conclusion by Bertero et al1 that skeletal muscle mitochondria are unable to withstand the ionic milieu of blood or the extracellular space, characterized by millimolar Ca2+ and Na+ concentrations, is unfounded and is not supported by the literature.The presence of intact mitochondria in blood containing physiological Ca2+ and Na+ concentrations has been shown by Al Amir Dache et al2 who have demonstrated the presence of cell-free mitochondria in human blood and also in cell culture media containing physiological calcium concentrations. These cell-free mitochondria maintain oxygen consumption and respiratory competency. The cell-free mitochondria are not encapsulated in extracellular vesicles or macrovesicles.2The ability of exogenous mitochondria to survive in 1.8 mMol Ca2+ was first demonstrated in 1982 by Clark and Shay3 who coincubated mammalian cells having chloromycetin sensitivity with isolated mitochondria from cells having chloromycetin resistance. The authors showed that the isolated mitochondria were taken up by endocytosis, transferring the antibiotic resistance to the recipient cells. These studies were performed in media containing 1.8 mMol Ca2+ and demonstrated that isolated mitochondria are taken up by recipient cells maintain function and confer protection not present in the recipient cells.Independent studies by King and Attardi,4 Katrangi et al,5 Pacak et al,6 Kessner et al,7 and Cowan et al8 have repeatedly demonstrated the uptake and functional integration of exogenous mitochondria into recipient cells in media containing 1.8 mMol Ca2+.In in vitro experiments using HeLap0 cells depleted of mitochondrial DNA (mtDNA) and having depleted ATP content due to loss of electron transport chain proteins encoded by mtDNA, it has been demonstrated that coincubation with mitochondria from cells containing intact mtDNA can rescue mitochondrial function and replace damaged mitochondrial DNA.8 All these in vitro studies were all performed in media containing 1.8 mmol/L Ca2+.The in vivo uptake and functional integration of exogenous mitochondria into cells has been demonstrated in a variety of animal models using mitochondria-specific labels that include DsRed (MitoTimer),7 iron oxide,8 transgenic labeled turbo green fluorescence,9 stable baculoviral fusion gene labeling of the mitochondrial matrix E1 alpha pyruvate dehydrogenase subunit,8 and 18F-rhodamine-6-G labeling.10,11 In all of these studies, intact mitochondria have been shown to be present and maintain function following transplantation in either blood or media containing physiological Ca2+ and Na+ concentrations.7–13In vivo heart studies have demonstrated that the transplantation of exogenous mitochondria into the heart delivered by either direct injection or by intracoronary injection increases total tissue ATP content, oxygen uptake, contractile function, upregulates differentially expressed proteins associated with mitochondrial function, and decreases infarct size.10,12The claims of Bertero et al1 suggesting the role of inflammation are also not supported. The transplanted mitochondria produce no inflammatory response.10,12,14,15 The transplanted mitochondria have no effect on coronary artery patency, are not proarrhythmic, and there is no direct or indirect and acute or chronic alloreactivity, allorecognition, or damage-associated molecular pattern molecule reaction.10,12,14,15Sources of FundingThis study was supported by The Richard A. and Susan F. Smith President's Innovation Award, The Sidman Family Foundation, the Michael B. Rukin Charitable Foundation, the Kenneth C. Griffin Charitable Research Fund, and the Boston Investment Conference.DisclosuresJ.D. McCully, S.M. Emani, and P.J. del Nido have patents pending for the isolation and usage of mitochondria.FootnotesFor Sources of Funding and Disclosures, see page e56.References1. Bertero E, O'Rourke B, Maack C. Mitochondria do not survive calcium overload during transplantation.Circ Res. 2020; 126:784–786. 10.1161/CIRCRESAHA.119.316291LinkGoogle Scholar2. Al Amir Dache Z, Otandault A, Tanos R, Pastor B, Meddeb R, Sanchez C, Arena G, Lasorsa L, Bennett A, Grange T, et al. Blood contains circulating cell-free respiratory competent mitochondria.FASEB J. 2020; 34:3616–3630. 10.1096/fj.201901917RRCrossrefMedlineGoogle Scholar3. Clark MA, Shay JW. Mitochondrial transformation of mammalian cells.Nature. 1982; 295:605–607. 10.1038/295605a0CrossrefMedlineGoogle Scholar4. King MP, Attardi G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA.Cell. 1988; 52:811–819. 10.1016/0092-8674(88)90423-0CrossrefMedlineGoogle Scholar5. Katrangi E, D'Souza G, Boddapati SV, Kulawiec M, Singh KK, Bigger B, Weissig V. Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function.Rejuvenation Res. 2007; 10:561–570. 10.1089/rej.2007.0575CrossrefMedlineGoogle Scholar6. Pacak CA, Preble JM, Kondo H, Seibel P, Levitsky S, Del Nido PJ, Cowan DB, McCully JD. Actin-dependent mitochondrial internalization in cardiomyocytes: evidence for rescue of mitochondrial function.Biol Open. 2015; 4:622–626. 10.1242/bio.201511478CrossrefMedlineGoogle Scholar7. Kesner EE, Saada-Reich A, Lorberboum-Galski H. Characteristics of mitochondrial transformation into human cells.Sci Rep. 2016; 6:26057. doi: 10.1038/srep26057CrossrefMedlineGoogle Scholar8. Cowan DB, Yao R, Thedsanamoorthy JK, Zurakowski D, del Nido PJ, McCully JD. Transit and fusion of exogenous mitochondria in human heart cells.Sci Rep. 2017; 7:17450. doi: 10.1038/s41598-017-17813-0CrossrefMedlineGoogle Scholar9. Gollihue JL, Patel SP, Eldahan KC, Cox DH, Donahue RR, Taylor BK, Sullivan PG, Rabchevsky AG. Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury.J Neurotrauma. 2018; 35:1800–1818. 10.1089/neu.2017.5605CrossrefMedlineGoogle Scholar10. Kaza AK, Wamala I, Friehs I, Kuebler JD, Rathod RH, Berra I, Ericsson M, Yao R, Thedsanamoorthy JK, Zurakowski D, et al. Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion.J Thorac Cardiovasc Surg. 2017; 153:934–943. 10.1016/j.jtcvs.2016.10.077CrossrefMedlineGoogle Scholar11. Masuzawa A, Black KM, Pacak CA, Ericsson M, Barnett RJ, Drumm C, Seth P, Bloch DB, Levitsky S, Cowan DB, et al. Transplantation of autologously-derived mitochondria protects the heart from ischemia-reperfusion injury.Am J Phys Heart Circ Physiol. 2013; 304:H966–H982. 10.1152/ajpheart.00883.2012CrossrefMedlineGoogle Scholar12. Shin B, Saeed MY, Esch JJ, Guariento A, Blitzer D, Moskowitzova K, Ramirez-Barbieri G, Orfany A, Thedsanamoorthy JK, Cowan DB, et al. Myocardial protection by intracoronary delivery of mitochondria: safety and efficacy in the ischemic myocardium.JACC Basic Transl Sci. 2019; 4:871–888. doi: 10.1016/j.jacbts.2019.08.007CrossrefMedlineGoogle Scholar13. Caicedo A, Aponte PM, Cabrera F, Hidalgo C, Khoury M. Artificial mitochondria transfer: current challenges, advances, and future applications.Stem Cells Int. 2017; 2017:7610414. doi: 10.1155/2017/7610414CrossrefMedlineGoogle Scholar14. Emani SM, McCully JD. Mitochondrial transplantation: applications for pediatric patients with congenital heart disease.Transl Pediatr. 2018; 7:169–175. 10.21037/tp.2018.02.02CrossrefMedlineGoogle Scholar15. Ramirez-Barbieri G, Moskowitzova K, Shin B, Blitzer D, Orfany A, Guariento A, Iken K, Friehs I, Zurakowski D, Del Nido PJ, et al. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria.Mitochondrion. 2019; 46:103–115. 10.1016/j.mito.2018.03.002CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Patel S, Michael F, Gollihue J, Hubbard W, Sullivan P and Rabchevsky A (2023) Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma, Mitochondrion, 10.1016/j.mito.2022.11.001, 68, (10-14), Online publication date: 1-Jan-2023. Hosseinian S, Ali Pour P and Kheradvar A (2022) Prospects of mitochondrial transplantation in clinical medicine: Aspirations and challenges, Mitochondrion, 10.1016/j.mito.2022.04.006, 65, (33-44), Online publication date: 1-Jul-2022. Lin M, Fang S, Hsu J, Huang C, Lee P, Huang C, Chen H, Lam C and Lee J (2022) Mitochondrial Transplantation Attenuates Neural Damage and Improves Locomotor Function After Traumatic Spinal Cord Injury in Rats, Frontiers in Neuroscience, 10.3389/fnins.2022.800883, 16 Velarde F, Ezquerra S, Delbruyere X, Caicedo A, Hidalgo Y and Khoury M (2022) Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact, Cellular and Molecular Life Sciences, 10.1007/s00018-022-04207-3, 79:3, Online publication date: 1-Mar-2022. Caicedo A, Zambrano K, Sanon S, Luis Vélez J, Montalvo M, Jara F, Moscoso S, Vélez P, Maldonado A and Velarde G (2021) The diversity and coexistence of extracellular mitochondria in circulation: A friend or foe of the immune system, Mitochondrion, 10.1016/j.mito.2021.02.014, 58, (270-284), Online publication date: 1-May-2021. Espino De la Fuente-Muñoz C and Arias C (2020) The therapeutic potential of mitochondrial transplantation for the treatment of neurodegenerative disorders, Reviews in the Neurosciences, 10.1515/revneuro-2020-0068, 32:2, (203-217), Online publication date: 23-Feb-2021., Online publication date: 1-Feb-2021. Sheeran F and Pepe S (2021) Targeting impaired bioenergetics in heart failure Clinical Bioenergetics, 10.1016/B978-0-12-819621-2.00024-3, (533-546), . Shanmughapriya S, Langford D and Natarajaseenivasan K (2020) Inter and Intracellular mitochondrial trafficking in health and disease, Ageing Research Reviews, 10.1016/j.arr.2020.101128, 62, (101128), Online publication date: 1-Sep-2020. Balcázar M, Cañizares S, Borja T, Pontón P, Bisiou S, Carabasse E, Bacilieri A, Canavese C, Diaz R, Cabrera F and Caicedo A (2020) Bases for Treating Skin Aging With Artificial Mitochondrial Transfer/Transplant (AMT/T), Frontiers in Bioengineering and Biotechnology, 10.3389/fbioe.2020.00919, 8 Rabchevsky A, Michael F and Patel S (2020) Mitochondria focused neurotherapeutics for spinal cord injury, Experimental Neurology, 10.1016/j.expneurol.2020.113332, 330, (113332), Online publication date: 1-Aug-2020. April 10, 2020Vol 126, Issue 8 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.316832PMID: 32271682 Originally publishedApril 9, 2020 PDF download Advertisement