In the high-stakes field of organ transplantation, the clock starts ticking the moment a donor organ is removed. A new review suggests that mitochondrial transplantation during machine perfusion could shift the paradigm from merely slowing deterioration to actively repairing damage, offering a potential route to rehabilitate organs that are currently deemed too damaged for use.
The review, published in Hepatobiliary & Pancreatic Diseases International (DOI:10.1016/j.hbpd.2025.10.003), was conducted by researchers from Wake Forest University, Wake Forest School of Medicine, Brown University, University Grenoble Alpes, and Grenoble Alpes University Hospital. It synthesizes preclinical evidence from heart, lung, and kidney models, where delivering healthy, energy-producing mitochondria during ex vivo perfusion improved contractility, oxygen exchange, tissue viability, and metabolic recovery.
Transplant medicine has long faced a critical shortage of donor organs, and many retrieved grafts are discarded because ischemia, cold storage, and reperfusion rapidly damage cells. Conventional preservation methods slow this decline but do not fully restore the mitochondrial machinery that produces energy and regulates survival, inflammation, and oxidative balance. Machine perfusion has created a window in which organs can be assessed and treated outside the body, but current systems focus on maintaining function rather than rebuilding it.
This new approach aims to change that. By delivering mitochondria during perfusion, the therapy could restore cellular metabolism, limit oxidative injury, and recover function before transplantation. The review maps evidence from donation after circulatory death (DCD) and donation after brain death (DBD) models. In pig hearts, autologous skeletal-muscle mitochondria delivered through the coronary circulation during normothermic perfusion improved contractile recovery, reduced oxygen use, and, in one study, cut infarct size by more than 75%. Human platelet-derived mitochondria also entered rat cardiomyocytes and supported membrane potential, ATP production, and cell viability while lowering reactive oxygen species.
In lungs, mitochondria added during ex vivo lung perfusion (EVLP) improved oxygenation, reduced pulmonary vascular resistance, and dampened inflammatory signals. Notably, mitochondria sourced from another individual or even another species produced benefits without signs of acute immune rejection in preclinical experiments. In porcine kidneys, autologous mitochondria stimulated metabolic activity and pathways linked to mitochondrial biogenesis and energy metabolism after prolonged perfusion.
The mechanism appears to involve mitochondria entering cells through endocytosis or membrane fusion, replacing damaged organelles, restoring oxidative phosphorylation, and rebalancing redox and inflammatory signaling. However, evidence for liver transplantation remains limited to related non-transplant injury models. The proposed clinical framework places this therapy across procurement, preservation, and transplantation, rather than at a single step.
The authors emphasize that the central idea is to stop treating donor organs as tissues that can only be protected from further decline. Mitochondria could instead 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 several organs is encouraging, but the field needs shared standards for mitochondrial quality, source, dose, delivery, and safety. The aim is not to replace preservation, but to transform preservation time into a controlled window for active recovery.
If validated clinically, mitochondrial transplantation could help rescue marginal hearts, lungs, kidneys, and possibly livers that would otherwise be declined, 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 to occur in the same workflow. Before that can happen, researchers must standardize isolation and characterization methods, determine the most suitable mitochondrial source, 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.
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