Scientists have created “nanoflowers” that nudge donor cells to produce more mitochondria, which can then be transferred to recipient cells to boost their mitochondrial function [1].
Mitochondrial transfer is difficult to improve
Energy is required for life, and most energy in our cells is produced by mitochondria. When these organelles start to falter, it’s a sign of trouble. Numerous diseases are linked to mitochondrial dysfunction, which is a hallmark of aging.
Intercellular mitochondrial transfer (IMT) is a natural rescue mechanism that is defined as stressed cells receiving healthy mitochondria from their neighbors, especially mesenchymal stem cells (MSCs), via tunneling nanotubes (TNTs), extracellular vesicles, or gap junction channels [2]. However, transfer rates are low, and most current methods to boost them are cumbersome and may involve genetic engineering.
In a new study from Texas A&M University, published in Proceedings of the National Academy of Sciences, the researchers describe a novel method for improving IMT, which involves some nanotechnological wizardry.
“Nanoflowers” boost mitochondrial output
The team looked for ways to improve mitogenesis in MSCs, reasoning that this might boost their ability to donate mitochondria. They started with molybdenum sulfide (MoS2) and subjected it to “defect engineering.” This process takes out some of the sulfur atoms, exposing molybdenum atoms that have electrons to donate. Molybdenum is a transition metal, which means it has variable oxidation states and can either donate or accept electrons depending on the context.
This unusual material can mimic the enzyme catalase, neutralizing ROS (reactive oxygen species). ROS react with various biomolecules, such as proteins, lipids, and DNA, damaging them and creating oxidative stress, which hurts mitochondrial function [3].
The exposed molybdenum atoms act as traps and catalysts for ROS molecules. For instance, when a molecule of hydrogen peroxide (H2O2), the most ubiquitous ROS, approaches the site, it accepts two electrons from a molybdenum atom, separating the extra oxygen atom from the peroxide and leaving behind water. When the next H2O2 molecule approaches the site, another oxygen atom pulls itself away from the peroxide and becomes bound to the first trapped oxygen atom, forming free diatomic oxygen (O2) and another molecule of water while returning the electrons to the molybdenum.
For further improvement, the researcher designed a process of MoS2 self-assembling into “nanoflowers”, delicate structures that greatly increase the material’s surface-to-weight ratio. MSCs were able to take nanoflowers up, which decreased ROS levels and improved mitochondrial output. After seven days of treatment, the amount of mitochondrial DNA, a marker of mitochondria abundance, doubled, and the production of ATP, the “energy currency” of the cell, increased as well.
“MoS2 nanoflowers with atomic vacancies activate the PGC-1α pathway by modulating cellular ROS levels and stimulating the SIRT1 signaling pathway,” the paper says. “This activation leads to increased mitochondrial biogenesis and enhanced cellular bioenergetics.” In other words, by clearing up ROS, nanoflowers triggered cells to signal that stress has decreased and mitochondria production can be ramped up.
“MitoFactories” to the rescue
To assess the effectiveness of IMT, the researchers induced mitochondrial damage in smooth muscle cells. “Nanoflower”-treated MSCs, which the researchers refer to as “MitoFactories,” were several-fold more effective in transferring their increased mitochondrial load into their damaged neighbors than untreated controls.
“We have trained healthy cells to share their spare batteries with weaker ones,” said Dr. Akhilesh K. Gaharwar, a professor of biomedical engineering and a senior author. “By increasing the number of mitochondria inside donor cells, we can help aging or damaged cells regain their vitality – without any genetic modification or drugs.”
“The several-fold increase in efficiency was more than we could have hoped for,” added Ph.D. student John Soukar, lead author of the paper. “It’s like giving an old electronic a new battery pack. Instead of tossing them out, we are plugging fully-charged batteries from healthy cells into diseased ones.”
Putting new mitochondria to work
The damaged recipient cells not just successfully accepted mitochondria from the “MitoFactories” via TNTs, but also put them to work, integrating them into their mitochondrial network. Enhanced mitochondrial transfer restored cellular function and survivability to a notable degree. Interestingly, undamaged recipient cells also benefited from improved TNT, showing higher respiratory capacity and ATP production.
“This is an early but exciting step toward recharging aging tissues using their own biological machinery,” Gaharwar said. “If we can safely boost this natural power-sharing system, it could one day help slow or even reverse some effects of cellular aging.”
The strictly in vitro design was an obvious limitation of this study. In a more realistic setting, especially in an aged, fibrotic tissue, donor cells might have been unable to approach the recipient’s cells to initiate IMT. However, this is an exciting proof of concept, and the researchers are optimistic.
“You could put the cells anywhere in the patient,” Soukar said. “For cardiomyopathy, you can treat cardiac cells directly – putting the stem cells directly in or near the heart. If you have muscular dystrophy, you can inject them right into the muscle. It’s pretty promising in terms of being able to be used for a whole wide variety of cases, and this is just the start. We could work on this forever and find new things and new disease treatments every day.”
Literature
[1] Soukar, J., Singh, K. A., Aviles, A., Hargett, S., Kaur, H., Foster, S., … & Gaharwar, A. K. (2025). Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency. Proceedings of the National Academy of Sciences, 122(43), e2505237122.
[2] Spees, J. L., Olson, S. D., Whitney, M. J., & Prockop, D. J. (2006). Mitochondrial transfer between cells can rescue aerobic respiration. Proceedings of the National Academy of Sciences, 103(5), 1283-1288.
[3] Guo, C., Sun, L., Chen, X., & Zhang, D. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural regeneration research, 8(21), 2003-2014.
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