Can supplying mitochondria from outside the cell treat damaged organs and diseases of energy metabolism? Mitochondrial transplantation, in which these ATP-producing organelles are isolated and administered, is being studied in fields ranging from organ protection to the treatment of genetic disorders. On November 2, 2026, Cheng and Liu published a peer-reviewed review in Frontiers in Physiology that focused mainly on kidney research. It distinguished between biological effects confirmed over the short term and long-term therapeutic benefits that have not yet been demonstrated.
Meanwhile, a study using vascular endothelial cells found that transplanted mitochondria do not necessarily keep functioning in the cell for a long time. Instead, the process by which they are broken down contributes to improved cell engraftment. This suggests that the effects of mitochondrial transplantation may not be explained simply by replenishing a cell's capacity to produce energy. Comparing clinical observations in people, life-extension effects in animal experiments and mechanisms within cells shows that even under the same name, "mitochondrial transplantation" differs greatly in what is supplied and in which changes are evaluated as therapeutic effects.
A Comparison of 24 Children Hints at Heart Recovery
In applications to the heart, researchers have studied a method in which mitochondria are isolated from a patient's own healthy tissue and administered to a heart damaged by interrupted blood flow. In the heart and other tissues, cells can be injured not only by ischemia, when blood flow is cut off, but also when blood flow resumes. This is known as ischemia-reperfusion injury. In patients with severely reduced heart function, extracorporeal membrane oxygenation (ECMO) may be used to support blood circulation and oxygen supply.
In a study reported by Guariento and colleagues in 2021 in The Journal of Thoracic and Cardiovascular Surgery, 24 pediatric patients who developed severe cardiac dysfunction after heart surgery were compared. The patients had been treated at a single institution between May 2002 and December 2018 and needed ECMO for severe cardiogenic shock caused by ischemia-reperfusion injury. The research team looked back through medical records and compared the courses of 10 patients who received autologous mitochondrial transplantation and 14 who did not.
According to the authors' abstract, "successful weaning," defined as coming off ECMO and staying off it for a week without reinstitution, was achieved in 8 of 10 patients (80%) in the transplant group and 4 of 14 (about 29%) in the control group. The difference between the groups was statistically significant (P = 0.02). However, successful weaning from ECMO is a different measure from overall survival, and this result cannot be equated with an improvement in patients' long-term outcomes. The study is also a retrospective comparison based on past medical records, not a clinical trial in which treatment was randomly assigned. What was observed was an association between mitochondrial transplantation and successful ECMO weaning; it cannot be concluded that the transplantation itself caused the recovery.
Breakdown of Transplanted Mitochondria Contributes to Better Engraftment
Can transplanting a small amount of mitochondria really supply enough energy to damaged tissue? In an article published on May 21, 2024, by Boston Children's Hospital, Sitaram Emani recalled that the explanation that transplanted mitochondria keep producing energy "didn't add up." Considering the amount of mitochondria actually administered, it is hard to explain the observed effects through energy supply alone.
A study published in Nature in 2024 by Lin and colleagues approached this question from another angle. In addition to experiments using human-derived vascular endothelial cells and mesenchymal stromal cells, the research team examined cell transplantation into immunodeficient mice. They found that transplanted mitochondria are not functionally integrated within recipient cells over the long term, but instead induce a mechanism called "mitophagy." Mitophagy is the process by which cells selectively break down mitochondria.
To test whether this degradation process is necessary for improved engraftment, the team also ran experiments suppressing the activity of related genes. When the function of PINK1 on the donor side or Parkin on the recipient side was suppressed, the engraftment-improving effect of mitochondrial transplantation was lost. Figure 5g of the paper compares engraftment seven days after transplantation, with 4 independent mice per condition and 8 in the condition in which mitochondria were added to endothelial cells. These are the numbers of subjects in the Figure 5g experiment, not the total number of animals used in the paper. In Figure 5d, which analyzed changes within cells, 30 cells were evaluated per group.
The different roles of the donor and recipient sides were also confirmed in experiments examining the intracellular structures involved in mitochondrial breakdown. Suppressing PINK1 on the recipient side did not change the clustering of LC3B, and suppressing Parkin on the donor side did not affect the formation of autophagosomes. The research team further reported that improved engraftment was also seen when donor mitochondria that had lost respiratory function, or mitochondria lacking mitochondrial DNA (mtDNA), were used.
These results support the idea that, at least in this endothelial cell experimental system, the intracellular processes involved in breaking down transplanted mitochondria, rather than continued energy production by them, underpin the improved engraftment. However, this mechanism does not necessarily work the same way in other organs or in genetic diseases. The authors also say that additional research is needed in cell systems other than blood vessels, and within the scope of what we could confirm, we found no results from an independent laboratory that directly replicated the study using the same endothelial cell system.
A 24-Hour Protective Effect Seen in Isolated Pig Kidneys
Research on protecting the organ itself uses different measures from those used for cell engraftment. In a study published in Annals of Surgery in 2023 by Rossi and colleagues, kidneys removed from four Yorkshire pigs were used to examine the tissue-protective effects of mitochondrial transplantation. After the isolated kidneys were placed in a warm ischemic state without blood flow at 37°C for 30 minutes, mitochondria isolated from each pig's own psoas muscle were injected into the renal artery. After waiting 30 minutes, the kidneys underwent ex vivo perfusion at 25°C for 24 hours.
In kidneys that received mitochondria, the TUNEL and 4-HNE staining measures used to assess tissue damage were lower. Perfusion resistance and flow, however, showed no differences, and the kidney injury markers NGAL and KIM-1 trended lower but did not reach statistical significance. In other words, some measures of tissue damage improved, but it was not confirmed that overall kidney function had recovered.
There is also an inconsistency in how the number of subjects is reported. The paper's methods state that there were 4 treated kidneys and 3 controls, and explain that one control kidney was excluded because of a faulty cannula. However, the note to Figure 4 gives the number of subjects as 5 kidneys, so the methods and the figure do not agree. For this reason, the total number of kidneys actually analyzed cannot be determined.
This study was also an experiment in which isolated kidneys were perfused outside the body; it did not transplant the treated kidneys into animals to examine survival or the course of kidney function. The review by Cheng and Liu published in November 2026 likewise points out that post-transplant survival has not been evaluated. The finding that tissue damage was reduced after 24 hours of ex vivo perfusion cannot be directly interpreted as an improvement in patients' kidney function or long-term graft survival after transplantation.
In Genetic Diseases, Life Extension in Mice and Exploratory Administration in Children Advance
The goals and methods of administration in mitochondrial transplantation differ between protecting organs injured by impaired blood flow and treating energy metabolism disorders caused by genetic abnormalities. In a study reported by Nakai, Varnum and colleagues in Nature Metabolism in 2024, mitochondria were administered to a mouse model of Leigh syndrome lacking the nuclear gene Ndufs4, and the effect on survival was examined. Within the same paper, research institutions in the United States and Japan each tested different donor materials and administration methods.
In an experiment in which 100 μg of isolated mouse-derived mitochondria was administered intraperitoneally, the median survival of the 27 control mice given the buffer PBS was 68 days, compared with 84 days in the 23 treated mice. In another experiment, 50 μg of HeLa cell-derived MRC-Q was administered intravenously once a week to mice aged 3 to 7 weeks. In this case there were 14 mice each in the control and treated groups, and median survival was 67.5 days and 80.5 days, respectively.
In both experiments the survival of the model mice was extended, but the loss of the Ndufs4 gene itself was not repaired. Although the two experiments were conducted at different institutions, they were reported within the same paper. Because the donor materials and routes of administration also differ, the survival times obtained cannot be simply compared to judge which method of administration is better.
In applications to people, approaches in which mitochondria are taken up by cells and those cells are returned to the patient are also being tried. A study published in Science Translational Medicine in 2022 by Jacoby and colleagues reported the compassionate use of this approach in six children with single large-scale mtDNA deletion syndrome. In the method, the patients' own CD34-positive hematopoietic cells took up mitochondria from their mothers, and the cells were then returned to the patients.
According to the authors' abstract published by the university, heteroplasmy in peripheral blood decreased in 4 of the 6 patients, and mtDNA levels after 6 to 12 months increased in all 6. Heteroplasmy refers to a state in which different mtDNA variants coexist within the same individual or cell. In addition, weight gain was seen in all 5 patients (of the 6 subjects) who had been underweight, and improvement in some motor tests was noted in 2 patients.
However, we could not confirm the full text of the paper, including before-and-after comparisons of measured values, so we cannot assess how large each change was. This study is an exploratory report of six patients without a control group, and the observed changes in symptoms cannot be attributed to the treatment. Nor is it a study design intended to demonstrate general safety. Taking the endothelial cell experiments and the review in the kidney field together, it becomes important to examine not only the amount of mitochondria administered and the immediate response, but also which cells they reach, how they are processed within the cells, and how well the function of those cells and organs is maintained afterward.
Challenges in Establishing Mitochondrial Transplantation as a Treatment
All five primary studies discussed so far were peer reviewed, but the subjects, materials administered, evaluation measures and conclusions that can be drawn from the results differ greatly. Cell engraftment, reduced tissue damage, weaning from ECMO and extended survival in model animals each measure a different outcome. The differences between studies and the verification still needed can be summarized as follows.
| Subjects and study design | Material administered | Main endpoints and results | Meaning of results and remaining challenges |
|---|---|---|---|
| Human-derived endothelial cells and immunodeficient mice. In Figure 5g, 4 mice per condition and 8 in the endothelial cells + mitochondria condition | Donor mitochondria | Engraftment 7 days after transplantation, and verification of the mechanism through gene suppression | Supports involvement of the breakdown process in the endothelial cell system. Verification in other cell systems and replication by independent institutions are needed |
| Ex vivo perfusion experiment using kidneys from 4 pigs | Autologous muscle-derived mitochondria | Tissue damage and perfusion measures at 24 hours. Some staining measures decreased | Suggests short-term tissue protection. Post-transplant kidney function and survival not evaluated |
| Single-center retrospective comparison of 24 children | Autologous mitochondria | Successful ECMO weaning: 8 of 10 in the transplant group, 4 of 14 in the control group | Association with successful weaning observed. Prospective controlled studies needed to confirm causation |
| Ndufs4-deficient mice. 27 controls and 23 treated; 14 each in a separate experiment | Isolated mouse-derived mitochondria, or HeLa cell-derived MRC-Q | Median survival. Extended from 68 to 84 days; in the separate experiment, from 67.5 to 80.5 days | Life extension confirmed in model animals. Efficacy in patients and optimal administration conditions not established |
| Compassionate use in 6 children without a control group | Autologous CD34-positive hematopoietic cells supplemented with maternal mitochondria | Course of peripheral blood measures, weight, motor tests and more | Exploratory clinical observation. Controlled studies needed to verify efficacy and safety |
Note: For the two studies of pediatric patients, we were able to check only the authors' abstracts. The pig isolated kidney study also has an inconsistency between its methods and figure legend in the number of subjects analyzed.
The mitochondrial breakdown mechanism confirmed in vascular endothelial cells cannot simply be applied as is to the Leigh syndrome model mice or to the administration of cells to children. As the review by Cheng and Liu laid out, it is necessary to verify separately whether mitochondria reach the target organ, which cells take them up, and what happens to them after uptake. Keeping the quality of the administered preparation consistent and confirming long-term safety are also challenges for clinical application. If clinical studies can confirm that short-term biological changes lead to recovery of organ function and improved long-term outcomes for patients, the evidence needed to judge which patients and diseases mitochondrial transplantation works for as a treatment will begin to take shape.