Transplant medicine continues to face a critical shortage of donor organs, with many retrieved grafts discarded due to damage from ischemia, cold storage, and reperfusion. Conventional preservation methods slow this decline but fail to restore the mitochondrial machinery essential for energy production, cell survival, and oxidative balance. Now, a new review suggests that mitochondrial transplantation during machine perfusion could shift the paradigm from passive preservation to active biological reconditioning, offering a way to rehabilitate organs previously deemed unusable.
Published in Hepatobiliary & Pancreatic Diseases International (DOI:10.1016/j.hbpd.2025.10.003) on October 14, 2025, the review synthesizes preclinical evidence from heart, lung, and kidney models, showing that delivering healthy mitochondria can improve contractility, oxygen exchange, tissue viability, and metabolic recovery. The research, conducted by teams from Wake Forest University, Brown University, and Grenoble Alpes University, outlines a framework for integrating this therapy into existing machine perfusion workflows.
In pig heart models of donation after circulatory death, autologous skeletal-muscle mitochondria delivered during normothermic perfusion improved contractile recovery and reduced oxygen consumption. One study reported a reduction in infarct size by more than 75%. 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 improved oxygenation and reduced pulmonary vascular resistance, with no signs of acute immune rejection 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 via endocytosis or membrane fusion, replace damaged organelles, restore oxidative phosphorylation, and rebalance redox and inflammatory signaling. However, evidence for liver transplantation remains limited to non-transplant injury models. The authors emphasize that the goal is not to replace preservation but to transform the preservation period 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," the authors stated. "Mitochondria could give transplant teams a practical way to address energy failure while an organ is already connected to a perfusion system." They noted that the consistency of benefits across several organs is encouraging, but the field now needs shared standards for mitochondrial quality, source, dose, delivery, and safety.
If validated clinically, mitochondrial transplantation could help rescue marginal hearts, lungs, kidneys, and possibly livers, while extending safe preservation windows and making 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 can happen, researchers must standardize isolation and characterization 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 will be essential to establish reproducibility, dosing, safety, and whether short-term metabolic recovery translates into durable graft function.
