Transplant medicine faces a persistent challenge: a limited supply of donor organs and the frequent discarding of retrieved grafts due to ischemic damage, cold storage injury, and reperfusion harm. Conventional preservation techniques only slow this decline, failing to restore the mitochondrial function that is critical for cellular energy production, survival, and oxidative balance. However, a novel strategy—mitochondrial transplantation during machine perfusion—offers a promising avenue to not just preserve but actively repair donor organs before transplantation.
A comprehensive review published in Hepatobiliary & Pancreatic Diseases International (DOI:10.1016/j.hbpd.2025.10.003) synthesizes preclinical evidence from heart, lung, and kidney models, demonstrating that delivering healthy mitochondria to organs during ex vivo perfusion can restore cellular metabolism, limit oxidative injury, and improve function. The review, authored by researchers from Wake Forest University, Wake Forest School of Medicine, Brown University, University Grenoble Alpes, and Grenoble Alpes University Hospital, outlines the potential of this approach to rehabilitate organs that are currently deemed too damaged for transplantation, thereby enlarging the donor pool.
The evidence is compelling. In pig hearts, autologous skeletal-muscle mitochondria delivered during normothermic perfusion improved contractile recovery and reduced oxygen consumption, with one study reporting a more than 75% reduction in infarct size. Human platelet-derived mitochondria also entered rat cardiomyocytes, supporting ATP production and cell viability while lowering reactive oxygen species. In lungs, mitochondria added during ex vivo lung perfusion improved oxygenation, reduced pulmonary vascular resistance, and dampened inflammatory signals, even when sourced from another individual or species, without acute immune rejection in preclinical experiments. In porcine kidneys, autologous mitochondria stimulated metabolic activity and pathways linked to mitochondrial biogenesis after prolonged perfusion.
Mechanistically, transplanted mitochondria may enter cells via endocytosis or membrane fusion, replacing damaged organelles and restoring oxidative phosphorylation. The review notes that the proposed clinical framework integrates this therapy across procurement, preservation, and transplantation stages, rather than as a single intervention. The authors emphasize that the goal is to transform preservation time into a controlled window for active recovery, not to replace existing preservation methods.
Despite the encouraging consistency of benefits across multiple organs, significant hurdles remain. The field needs standardized protocols for mitochondrial quality, source, dose, and delivery, as well as clarity on long-term fate and immune effects. Researchers must determine whether autologous, allogeneic, or xenogeneic mitochondria are most suitable, and large-animal studies and carefully designed human trials are essential to establish reproducibility, safety, and durable graft function.
If validated clinically, mitochondrial transplantation could rescue marginal hearts, lungs, kidneys, and potentially livers, extend safe preservation windows, and facilitate long-distance organ sharing. It could also be integrated into existing machine-perfusion platforms, allowing treatment and viability testing in the same workflow. As the authors conclude, the central idea is to stop treating donor organs as tissues that can only be protected from further decline, and instead use mitochondria to give transplant teams a practical way to address energy failure while the organ is already connected to a perfusion system. This approach holds the potential to shift transplant medicine from passive storage toward biological reconditioning, ultimately improving outcomes for patients on transplant waiting lists.
