Mitochondrial Transplantation Offers New Hope for Repairing Donor Organs

When a donor organ is removed for transplantation, standard preservation becomes a race against time to minimize ischemic injury. According to a collaborative review published by researchers from Wake Forest University, Wake Forest School of Medicine, Brown University, University Grenoble Alpes, and Grenoble Alpes University Hospital in Hepatobiliary & Pancreatic Diseases International, mitochondrial transplantation could change that race from slowing tissue deterioration to actively repairing cellular damage. Delivered during machine perfusion, healthy mitochondria aim to restore cellular metabolism, limit oxidative stress, and recover organ function prior to surgical implantation. The paper, DOI: 10.1016/j.hbpd.2025.10.003, brings together preclinical evidence from heart, lung, and kidney models, highlighting a potential route to rehabilitate marginal organs, expand the donor pool, and move transplant medicine beyond passive storage.

• Mitochondrial delivery during ex vivo perfusion aims to actively rehabilitate donor organs rather than merely slow cellular decline during cold storage.
• Preclinical models across heart, lung, and kidney tissue show improvements in oxygen exchange, metabolic recovery, and tissue viability.
• Researchers mapped evidence from donation after circulatory death and brain death models, identifying technical steps required before human clinical trials.

Transplantation medicine remains severely constrained by a limited supply of viable donor grafts. Many retrieved organs are discarded because ischemia, cold storage, and subsequent reperfusion rapidly damage cellular structures. Conventional preservation methods slow this decline, but they do not fully restore the complex mitochondrial machinery responsible for generating adenosine triphosphate, regulating cell survival, modulating inflammation, and maintaining oxidative balance. While machine perfusion systems have created a reliable window outside the body to assess organs, most current setups prioritize baseline maintenance over active biological reconditioning. Addressing this clinical gap requires safer and more consistent methods to deliver functional mitochondria to marginal donor organs before they are implanted in recipients.

Preclinical Evidence Across Organ Models

The review published in Hepatobiliary & Pancreatic Diseases International synthesizes data from multiple animal models to evaluate how mitochondrial delivery alters organ viability. In pig heart models, researchers delivered autologous skeletal-muscle mitochondria directly through the coronary circulation during normothermic perfusion. This intervention improved contractile recovery, reduced oxygen consumption, and cut infarct size by more than 75% in specific trials, though investigators observed that an additional dose provided no further benefit. Additional experiments involving human platelet-derived mitochondria demonstrated successful entry into rat cardiomyocytes, supporting membrane potential, ATP production, and overall cell viability while suppressing reactive oxygen species.

Parallel benefits emerged in pulmonary models. When isolated mitochondria were added during ex vivo lung perfusion, treated organs exhibited improved oxygenation, reduced pulmonary vascular resistance, and dampened inflammatory signaling. Notably, mitochondria sourced from different individuals or across species boundaries still delivered protective effects without triggering acute immune rejection in preclinical setups. In porcine kidney experiments, administration of autologous mitochondria stimulated metabolic activity and upregulated pathways associated with mitochondrial biogenesis and energy regulation following prolonged periods of perfusion.

Mechanisms of Action and Proposed Clinical Integration

Cellular uptake of transplanted mitochondria occurs primarily through endocytosis or direct membrane fusion. Once inside damaged cells, these healthy organelles replace dysfunctional counterparts, restore oxidative phosphorylation, and rebalance redox and inflammatory pathways. The authors of the review propose a comprehensive clinical framework that integrates mitochondrial therapy across multiple stages of transplantation—from initial organ procurement and ex vivo preservation to final surgical implantation—rather than confining the intervention to a single step.

Despite promising preclinical results, evidence regarding liver transplantation currently remains limited to related non-transplant injury models. Investigators emphasize that key technical hurdles and safety profiles must be thoroughly resolved before these strategies transition into standard human clinical workflows.