Xenotransplantation of mitochondria: A novel strategy to alleviate ischemia-reperfusion injury during ex vivo lung perfusion

Abstract

Background: Ischemia-reperfusion injury (IRI) plays a crucial role in the development of primary graft dysfunction (PGD) following lung transplantation. A promising novel approach to optimize donor organs before transplantation and reduce the incidence of PGD is mitochondrial transplantation.

Methods: In this study, we explored the delivery of isolated mitochondria in 4 hours ex vivo lung perfusion (EVLP) before transplantation as a means to mitigate IRI. To provide a fresh and viable source of mitochondria, as well as to streamline the workflow without the need for donor muscle biopsies, we investigated the impact of autologous, allogeneic, and xenogeneic mitochondrial transplantation. In the xenogeneic settings, isolated mitochondria from mouse liver were utilized while autologous and allogeneic sources came from pig skeletal muscle biopsies.

Results: Treatment with mitochondrial transplantation increased the P/F ratio and reduced pulmonary peak pressure of the lungs during EVLP, compared to lungs without any mitochondrial transplantation, indicating IRI mitigation. Extensive investigations using advanced light and scanning electron microscopy did not reveal evidence of acute rejection in any of the groups, indicating safe xenotransplantation of mitochondria.

Conclusions: Future work is needed to further explore this novel therapy for combating IRI in lung transplantation, where xenotransplantation of mitochondria may serve as a fresh, viable source to reduce IRI.

Keywords: ATMP; ex vivo lung perfusion; ischemia-reperfusion injury; mitochondria; xenotransplantation.