Mitochondria, also known as the powerhouses of the cell, are essential for cell survival, repair, and adaptation. Not only do they generate most of the energy needed during a cell's life, but they also regulate cell death, calcium balance, and responses to stress. When mitochondria fail, which is a common feature of neurodegenerative diseases and many inflammatory and metabolic disorders, cells lose their ability to meet energy demands and maintain internal stability. To tackle such problems, researchers are currently exploring therapies that aim to directly restore mitochondrial function. A promising approach is mitochondrial transplantation, an emerging therapeutic concept in which functional mitochondria are isolated and delivered to compromised cells.
Despite growing interest and encouraging results in recent animal and cell-based studies, a fundamental problem has slowed progress in this field: scientists do not yet fully understand how transplanted mitochondria interact with recipient cells. Do cells actively take up these organelles, or do mitochondria exert their effects from outside the cell? If mitochondria do enter cells, by what mechanisms do they cross the cell membrane, and do they remain functional once inside? Without clear answers to these questions, it is difficult to optimize mitochondrial transplantation techniques, assess their safety and effectiveness, and ultimately use them in a clinical setting.
In a recent study, published in Volume 15 of Scientific Reports on December 29, 2025, a research team led by Associate Professor Kosuke Kusamori from the Department of Life Sciences and Pharmaceutical Sciences, Tokyo University of Science (TUS), Japan, directly addressed this knowledge gap. They focused on mesenchymal stromal cells (MSCs), a type of cell widely studied in regenerative medicine, with significant biological properties and expanded therapeutic applicability. Combining detailed biochemical measurements with multiple advanced imaging techniques, the team set out to determine if and how isolated mitochondria are taken up by MSCs, and whether these mitochondria remain biologically active after internalization. This work was co-authored by fourth-year doctoral student Ms. Mai Kanai, fifth-year student Ms. Miyabi Goto, Dr. Shoko Itakura, and Dr. Makiya Nishikawa, all from TUS.
The researchers first isolated mitochondria from MSCs using a method designed to preserve their structural integrity. They confirmed that the isolated mitochondria were free of contamination by other cellular components and retained the ability to produce adenosine triphosphate (ATP). When these mitochondria were supplied to living cells, the team observed clear benefits. Treated cells exhibited increased proliferation and were better able to withstand chemical and oxidative stress. Measurements of oxygen consumption—a standard way to assess mitochondrial respiration—revealed that the supplied mitochondria enhanced overall cellular energy metabolism. "Mitochondrial treatment increased the respiration rate, ATP production rate, and maximal respiratory capacity of MSCs in a concentration-dependent manner. These findings suggest that the isolated mitochondria not only preserve their intrinsic bioenergetic activity but also exert proliferative and cytoprotective effects on MSCs and hepatocytes," remarks Dr. Kusamori.
To determine whether these effects required the supplied mitochondria to actually enter the cells, the team tracked mitochondrial uptake over time. Using fluorescence microscopy, confocal microscopy, flow cytometry, and label-free live imaging, they showed that mitochondria were gradually internalized by MSCs over several hours. Electron microscopy provided further confirmation, revealing mitochondria-like structures enclosed within membrane-bound vesicles inside the cells. Then, by selectively blocking different endocytic pathways, the researchers demonstrated that MSCs rely on multiple endocytic mechanisms to internalize mitochondria, rather than a single dominant route.
Taken together, these findings shed light on the processes that drive mitochondrial uptake and how it can prove beneficial for cells. "This study is an important achievement that provides a scientific foundation for the development of new therapies based on mitochondrial transplantation. We will pave the way for a new medical field called mitochondrial therapy, which directly supplements cellular energy functions and contributes to the realization of safer and more sustainable treatments," concludes Dr. Kusamori.
These findings support mitochondrial-based therapy, though further research is needed before clinical use. Notably, understanding how mitochondria enter cells may allow researchers to enhance uptake efficiency and tailor delivery strategies to different cell types.
Unlike stem cell or gene therapy, mitochondrial transplantation does not change genetic identity; it restores bioenergetics by supplying functional organelles, offering a rapid option for acute or localized mitochondrial dysfunction.
Mitochondrial transplantation therapy could be especially valuable for conditions driven by mitochondrial dysfunction, such as toxin-induced liver injury, ischemia–reperfusion-related conditions caused by heart attack or stroke, and Parkinson's and Alzheimer's diseases. More broadly, it may benefit ischemic tissue injury, neurodegenerative disorders, and age-related conditions in which mitochondrial activity is compromised. Although many challenges remain before clinical translation, including confirming long-term safety and efficacy, controlling mitochondrial uptake and distribution in different tissues, avoiding unwanted immune responses, and ensuring the purity, consistency, and functional integrity of isolated mitochondria, this work puts us one step closer to a transformative therapeutic platform—one that holds much promise in next-generation regenerative medicine and anti-aging treatments.
Importantly, mitochondrial transplantation is still in the preclinical stage and requires years of further validation in disease models before human clinical trials can begin.
