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. Existing preservation methods slow this deterioration but do not restore the mitochondrial function essential for cellular energy and survival. A new review suggests that mitochondrial transplantation during machine perfusion could shift the paradigm from merely preserving organs to actively repairing them.
Published in Hepatobiliary & Pancreatic Diseases International (DOI:10.1016/j.hbpd.2025.10.003), the review synthesizes evidence from preclinical heart, lung, and kidney models, demonstrating that delivering healthy mitochondria can improve contractility, oxygenation, tissue viability, and metabolic recovery. The researchers, from institutions including Wake Forest University and Grenoble Alpes University, argue that this approach could rehabilitate organs currently deemed too damaged for transplant, thereby enlarging the donor pool.
The review details findings from donation after circulatory death (DCD) and donation after brain death (DBD) models. In pig hearts, autologous mitochondria delivered during normothermic perfusion improved contractile recovery and reduced infarct size by over 75% in one study. Human platelet-derived mitochondria also enhanced ATP production and cell viability in rat hearts. In lung models, mitochondria added during ex vivo lung perfusion (EVLP) improved oxygenation and reduced inflammatory signals, even when sourced from another individual or species, without acute immune rejection. Porcine kidneys showed increased metabolic activity and mitochondrial biogenesis after receiving autologous mitochondria.
Mechanistically, transplanted mitochondria may enter cells via endocytosis or membrane fusion, replacing damaged organelles and restoring oxidative phosphorylation. The proposed clinical framework integrates this therapy across procurement, preservation, and transplantation, transforming the perfusion period into an opportunity for active recovery.
The authors emphasize the need for standardized protocols for mitochondrial quality, source, dose, and delivery. They note that while the consistency of benefits across organs is encouraging, the field must address safety and long-term effects. If validated clinically, mitochondrial transplantation could extend preservation windows, facilitate long-distance organ sharing, and be seamlessly incorporated into existing machine-perfusion platforms.
Before human trials, researchers must resolve key questions: optimal mitochondrial source (autologous, allogeneic, or xenogeneic), delivery methods, and long-term immune consequences. Large-animal studies will be crucial to establish reproducibility and dosing. The review underscores that the aim is not to replace preservation but to enhance it, turning downtime into a therapeutic window.
This strategy represents a significant departure from conventional organ preservation, offering a potential solution to the organ shortage crisis. By actively repairing mitochondrial function, it may rescue marginal organs and improve transplant outcomes, ultimately saving more lives.
