Targeting Mitochondria in Blood Stem Cells Could Treat Clonal Hematopoiesis

Research led by scientists at The Jackson Laboratory (JAX) has uncovered the mechanism responsible for the unchecked growth of blood stem cells, which accumulate genetic mutations as we age. These mutations increase the cells’ ability to replicate, creating a fertile environment for clonal hematopoiesis, a condition that significantly raises the risk of heart disease, blood cancers and other age-related illnesses. The study, published today in Nature Communications, also identifies a way to block this growth, offering potential for future therapeutic interventions.

The role of the Dnmt3a mutation in aging

The study, led by Dr. Jennifer Trowbridge, professor and The Dattels Family Chair at JAX, focuses on the mutation in the Dnmt3a gene, which is frequently found in aging blood stem cells and is associated with blood cancers. The researchers developed a mouse model carrying this mutation to understand why cells with Dnmt3a gain a competitive advantage over normal blood stem cells. Their findings reveal that mutated cells have mitochondria that produce energy at double the capacity of normal cells. These enhanced mitochondria give the mutated stem cells a significant growth advantage, allowing them to replicate more readily and contributing to the development of clonal hematopoiesis.

“This work gives us a new window into how and why blood stem cells change with age and how that sets up an increased risk of diseases like cancer, diabetes and heart disease,” said Trowbridge. 

The mutation-induced alteration in stem cells fuels their unchecked growth and the production of inflammatory molecules, which disrupt normal blood production and impair immune function.

Targeting mitochondrial activity to halt unchecked growth

Given that the mutated blood stem cells rely heavily on their hyperactive mitochondria for energy, the researchers identified this metabolic pathway as a potential vulnerability. The team tested the effects of molecules designed to disrupt mitochondrial function – MitoQ and d-TPP – on the mutated cells. The results were promising: within a few days of treatment, approximately half of the mutant cells died, and the remaining cells saw their energy production reduced to normal levels. In contrast, normal cells, which do not depend on the same metabolic pathway, were unaffected.

“Seeing this selective vulnerability where mutated cells were weakened, but normal stem cells are fine, was really exciting,” said Trowbridge.

Metformin as a potential treatment

In addition to mitochondrial-targeting drugs, the team also explored the use of metformin, a common treatment for type 2 diabetes, to see if it could diminish the competitive advantage of mutated blood stem cells. The study, co-published today in Nature, found that metformin also reduced the growth advantage of stem cells with the Dnmt3a mutation. This suggests that metformin may be another promising approach for tackling clonal hematopoiesis and its associated risks, including blood cancers and heart disease.

Implications for human health

The promising results from the mouse model were mirrored in human blood stem cells engineered with the Dnmt3a mutation, indicating that mitochondrial-targeting drugs could be effective for treating humans with clonal hematopoiesis. While these findings open up new possibilities for preventing blood cancers and other age-related diseases, further research is necessary to evaluate the broader application of these drugs and their effects on different mutations observed in clonal hematopoiesis.

This research provides insights into how aging-related genetic mutations drive the unchecked growth of blood stem cells, contributing to clonal hematopoiesis and increasing the risk of severe diseases. By targeting the mitochondria of these mutated cells, scientists may have identified a novel approach to selectively weaken harmful cells while preserving normal blood stem cells, offering hope for the development of effective therapies for age-associated illnesses.

Reference: Young KA, Hosseini M, Mistry JJ, et al. Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nat Comm 2025;16(1):3306. doi: 10.1038/s41467-025-57238-2

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