Commentary: Mitochondrial transplantation for ischemia-reperfusion injury—a new revolution or tilting at windmills?

Abstract

Central MessageAutologous mitochondrial transplantation is an elegant concept with a promising translational application.See Article page 992. Autologous mitochondrial transplantation is an elegant concept with a promising translational application. See Article page 992. The last 2 decades have been marked by explosive and exponential research activity aimed at regeneration and improvement of myocardial function in children. Stem cell therapies have been extensively trialed in the setting of ischemia-reperfusion injury, albeit without widespread clinical application.1Sano S. Sano T. Ishigami S. Ito T. Cardiac stem cell therapy: does a newborn infant's heart have infinite potential for stem cell therapy?.J Thorac Cardiovasc Surg. September 14, 2020; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (3) Google Scholar In a detailed study recently published in Nature, injection of alive or dead stem cells or a chemical inducer of innate immunity all resulted in activation of innate immunity and improvement in myocardial function.2Vagnozzi R.J. Maillet M. Sargent M.A. Khalil H. Johansen A.K.Z. Schwanekamp J.A. et al.An acute immune response underlies the benefit of cardiac stem cell therapy.Nature. 2020; 577: 405-409Crossref PubMed Scopus (227) Google Scholar This suggests that the beneficial effects of stem cell therapy are likely related to activation of the innate immune response, rather than to stem cell engraftment.2Vagnozzi R.J. Maillet M. Sargent M.A. Khalil H. Johansen A.K.Z. Schwanekamp J.A. et al.An acute immune response underlies the benefit of cardiac stem cell therapy.Nature. 2020; 577: 405-409Crossref PubMed Scopus (227) Google Scholar,3Epstein J.A. Rosenthal N. Feldman A.M. Teasing the immune system to repair the heart.N Engl J Med. 2020; 382: 1660-1662Crossref PubMed Scopus (4) Google Scholar An elegant and more targeted approach to myocardial regeneration—autologous mitochondria transplantation—has been developed by the Boston group. This group previously demonstrated that the majority of transplanted exogenous mitochondria fuse with the endogenous mitochondrial network (Figure 1), with associated increase in adenosine triphosphate production.4Cowan D.B. Yao R. Thedsanamoorthy J.K. Zurakowski D. del Nido P.J. McCully J.D. Transit and integration of extracellular mitochondria in human heart cells.Sci Rep. 2017; 7: 17450Crossref PubMed Scopus (71) Google Scholar In a porcine model of ischemia-reperfusion injury, mitochondrial transplantation was associated with decreased markers of myocardial injury and smaller infarct size compared with control animals. Furthermore, the presence of transplanted mitochondria was demonstrated for up to 4 weeks.5Kaza A.K. Wamala I. Friehs I. Kuebler J.D. Rathod R.H. Berra I. et al.Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/reperfusion.J Thorac Cardiovasc Surg. 2017; 153: 934-943Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar The same group previously published their initial clinical experience with this autologous mitochondria transplantation technique in 5 children on extracorporeal membrane oxygenation (ECMO) support, demonstrating that mitochondrial transplantation is feasible and apparently safe.6Emani S.M. Piekarski B.L. Harrild D. Del Nido P.J. McCully J.D. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury.J Thorac Cardiovasc Surg. 2017; 154: 286-289Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar In this issue of the Journal, the Boston group report their further experience with injection of autologous mitochondria into the myocardium of children with ischemia-reperfusion injury.7Guariento A. Piekarski B.L. Doulamis I.P. Blitzer D. Ferraro A.M. Harrild D.M. et al.Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury.J Thorac Cardiovasc Surg. 2021; 162: 992-1001Abstract Full Text Full Text PDF Scopus (17) Google Scholar In 10 patients who required ECMO support following ischemia-reperfusion injury, autologous mitochondria were isolated from nonischemic rectus abdominis muscle and injected into the ischemic myocardium. These 10 subjects were compared with 14 historical controls. The patients treated with mitochondrial transplantation were more likely to successfully wean from ECMO and had better cardiovascular event-free survival and improved myocardial strain. Interestingly, the median age was lower in the treatment group (0.4 months [range 0.1-3.9 months] vs 11 months [range, 0.2-51 months]), although the difference did not reach statistical significance. The lack of statistical difference could be due to the small numbers alone. It should be remembered that mammalian neonatal myocardium has transient regenerative potential8Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. et al.Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1572) Google Scholar; thus, it is likely that the myocardium has a greater capacity for recovery in younger children compared with older children. The results of the study are further obscured by the fact that all 14 patients in the nontreatment group were from a historical control cohort operated on between 2002 and 2015, whereas all 10 patients in the treatment group were operated on between 2015 and 2018. Some era bias could have affected the results. Of note, there are currently at least 8 ongoing trials investigating the effect of stem cells in children with heart disease.1Sano S. Sano T. Ishigami S. Ito T. Cardiac stem cell therapy: does a newborn infant's heart have infinite potential for stem cell therapy?.J Thorac Cardiovasc Surg. September 14, 2020; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (3) Google Scholar It is time for this promising concept of autologous mitochondria transplantation to be subjected to a randomized controlled trial. The great effort expended on research into protection against ischemia-reperfusion injury and myocardial regeneration over the last decades has proven somewhat quixotic, without delivering the expected clinical translation. One may hope that mitochondrial transplantation will not be lost in translation. Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injuryThe Journal of Thoracic and Cardiovascular SurgeryVol. 162Issue 3PreviewTo report outcomes in a pilot study of autologous mitochondrial transplantation (MT) in pediatric patients requiring postcardiotomy extracorporeal membrane oxygenation (ECMO) for severe refractory cardiogenic shock after ischemia-reperfusion injury (IRI). Full-Text PDF