Background: Ischemia-reperfusion injury (IRI) significantly contributes to the onset of primary graft dysfunction (PGD) in lung transplant recipients. To enhance pre-transplant lung quality and diminish post-transplant PGD incidence, considerable efforts have been devoted to investigating novel therapeutic interventions aimed at mitigating IRI and ensuring optimal lung function post-transplantation. One such intervention involves the administration of isolated mitochondria to the lungs prior to transplantation. However, the practicality of utilizing isolated mitochondria as an off-the-shelf therapy is constrained, as these mitochondria must be utilized promptly, typically within an hour after isolation, to ensure the transplantation of viable, high-quality mitochondria. To address the challenge of sourcing fresh, high-quality mitochondria without resorting to recipient biopsies, we explored the potential of mitochondrial xenotransplantation.
Method: Lungs exhibiting ischemia-reperfusion injury were partitioned into two lobes, and two simultaneous ex vivo lung perfusion (EVLP) procedures were conducted to enable a direct and optimal comparison of various treatments. In this study, four distinct groups were evaluated: treatment involving autologous, allogenic, and xenogeneic isolated mitochondrial transplantation into normothermic EVLP using porcine lungs, juxtaposed with a control group receiving no treatment. In the xenogeneic context, isolated mitochondria sourced from mouse liver were employed and transplanted into porcine lungs during EVLP.
Results: Mitochondrial transplantation significantly elevated the PaO2/FiO2 ratio and diminished pulmonary vascular resistance in lungs undergoing EVLP, compared to lungs devoid of mitochondrial transplantation. Although a positive trend in the PaO2/FiO2 ratio was observed in lungs receiving xenogeneic mitochondrial transplantation relative to the other three groups, statistical significance was not attained. Extensive assessments utilizing advanced light and scanning electron microscopy revealed no indications of acute rejection in any of the experimental groups.
Conclusion: Mitochondrial transplantation effectively attenuated IRI, with mitochondria sourced from different origins—autologous, allogenic, and xenogeneic—exhibiting no signs of acute rejection or inflammation, thus suggesting the safety of mitochondrial xenotransplantation. Further investigations are warranted to delve deeper into this therapeutic approach for combating IRI in lung transplantation, where xenotransplantation of mitochondria may emerge as a promising strategy for procuring viable mitochondria and mitigating IRI.