Transplant medicine faces a persistent challenge: many donor organs are discarded because ischemia, cold storage, and reperfusion cause irreversible cellular damage. While machine perfusion has extended preservation times, it largely maintains organs rather than repairing them. A new review, published in Hepatobiliary & Pancreatic Diseases International, proposes that mitochondrial transplantation during ex vivo perfusion could shift the paradigm from passive preservation to active biological reconditioning.
The review, led by researchers from Wake Forest University, Wake Forest School of Medicine, Brown University, University Grenoble Alpes, and Grenoble Alpes University Hospital, synthesizes preclinical evidence suggesting that delivering healthy mitochondria to donor organs could restore cellular metabolism, reduce oxidative injury, and improve function before transplantation. The findings were published online on October 14, 2025, and appear in the June 2026 issue (DOI:10.1016/j.hbpd.2025.10.003).
In heart models, autologous skeletal-muscle mitochondria delivered via coronary circulation 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 lung models, mitochondria added during ex vivo lung perfusion enhanced oxygenation, reduced pulmonary vascular resistance, and dampened inflammatory signals, with no acute immune rejection observed even when mitochondria were from another individual or species. Porcine kidney studies showed that autologous mitochondria stimulated metabolic activity and pathways linked to mitochondrial biogenesis after prolonged perfusion.
Mechanistically, transplanted mitochondria may enter cells through endocytosis or membrane fusion, replacing damaged organelles and restoring oxidative phosphorylation. This approach could help rebalance redox and inflammatory signaling, addressing the energy failure that underlies much of the damage seen in donor organs. However, evidence for liver transplantation remains limited to non-transplant injury models, highlighting the need for further research.
The authors emphasize that the goal is not to replace current preservation methods but to transform preservation time into a controlled window for active recovery. "The central idea is to stop treating donor organs as tissues that can only be protected from further decline," they note. "Mitochondria could give transplant teams a practical way to address energy failure while an organ is already connected to a perfusion system." The consistency of benefits across heart, lung, and kidney models is encouraging, but the field requires shared standards for mitochondrial quality, source, dose, delivery, and safety.
If validated clinically, this strategy could rescue marginal organs that would otherwise be declined, extend safe preservation windows, and make long-distance organ sharing more feasible. It could also be integrated into existing machine-perfusion platforms, allowing treatment and viability testing in the same workflow. Before that, researchers must standardize isolation methods, determine the most suitable mitochondrial source (autologous, allogeneic, or xenogeneic), and clarify long-term fate and immune effects. Large-animal studies and carefully designed human trials are essential to establish reproducibility, dosing, safety, and whether short-term metabolic recovery translates into durable graft function.
