Clonal hematopoiesis, a condition linked to numerous age-related disorders, can be caused by overachieving mitochondria, and it may be susceptible to drugs such as MitoQ and metformin [1].
The attack of the clones
The human body constantly produces vast numbers of blood cells from hematopoietic stem and progenitor cells (HSPCs). Over time, some HSPCs may acquire mutations that make them better at reproduction. These cells’ progeny then overwhelm the blood cell population in a phenomenon known as clonal hematopoiesis (CH). CH is rare in people under 40, but its prevalence rises steadily with age, reaching about 50% in 80-year-olds. Most centenarians are thought to be affected.
CH has been tied to elevated risks of blood cancers, cardiovascular disease, and immune exhaustion [2]. The same mutations that drive CH usually cause HSPCs to produce more myeloid cells, which include most innate immune cells, and fewer lymphocytes, which are predominantly B and T cells that power adaptive immunity.
An immune system affected by myeloid skewing tends to produce excessive inflammatory responses yet is less competent at actually fighting pathogens. Many geroscientists believe that CH plays a major role in age-related immunosenescence and chronic low-grade inflammation (inflammaging). It might even be one of the factors limiting human lifespan to about 120 years.
Supercharged mitochondria
In this new study published in Nature Communications, scientists from the Jackson Laboratory (JAX) focused on the most prevalent CH-related mutation. It is located in the gene DNMT3A, which encodes DNA methyltransferase. The researchers’ goal was to understand why this mutation confers a competitive advantage.
The researchers used a mouse model that mimicked the aged bone marrow microenvironment by downregulating insulin-like growth factor 1 (IGF-1), which supports HSPC maintenance. After depleting the original immune cells in those mice, HSPCs were transplanted from wild-type mice and from mice carrying the DNMT3A mutation. This created a competition between the two cell types, which the mutation-carrying cells easily won.
Looking for reasons behind this superior performance, the researchers found that the mutation improved mitochondrial efficiency by causing DNA hypomethylation and overexpression of genes related to oxidative phosphorylation, the primary form of cellular energy production. Indeed, mitochondria in mutated cells had increased membrane potential, suggesting enhanced function. The mutation essentially doubled the cells’ energy output.
“This was really unexpected,” said Jennifer Trowbridge, professor and Dattels Family Chair at JAX. “This gene [DNMT3A] was not previously known to impact metabolism or mitochondria.”
MitoQ and metformin calm things down
This advantage, however, turned out to be the mutated cells’ Achilles’ heel. Their elevated membrane potential made them especially vulnerable to inhibition of the electron transport chain, the heart of oxidative phosphorylation, by molecules such as MitoQ.
MitoQ is better known as an antioxidant that supposedly boosts mitochondrial function. However, in this context, the increased mitochondrial membrane potential caused excessive accumulation of MitoQ in the mitochondrial matrix, reducing function instead. In mutated cells, MitoQ also upregulated genes related to apoptosis (programmed cell death). The treatment caused about half of the mutated cells to die off and restored normal respiration in the rest.
“In contrast,” the paper notes, “transcriptional changes induced by MitoQ in control HSCs reflected reduced reactive oxygen species and increased mitochondrial function, consistent with MitoQ being an antioxidant that has a beneficial effect on metabolism and function of aged wild-type HSCs.”
Essentially, the treatment nullified the competitive advantage of mutated cells while also improving the health of wild-type cells: a win-win situation. “Seeing this selective vulnerability where mutated cells were weakened, but normal stem cells are fine, was really exciting,” said Trowbridge.
The researchers extended their findings to human cells. Here, too, the addition of MitoQ significantly reduced the competitive growth advantage of cells with DNMT3A knocked down.
In a separate paper published in Nature, the team reported a similar effect for metformin, an anti-diabetes drug that has gained fame as a potential geroprotector [3]. While scientists are still not entirely sure how it works, this study found that it inhibits mitochondrial complex I of the electron transport chain. The resulting metabolic stress hit DNMT3A-mutant HSPCs harder, as they rely more heavily on oxidative phosphorylation than wild-type cells.
“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,” Trowbridge said. “It also points toward a new opportunity to intervene and potentially prevent age-associated conditions not only in the blood but everywhere the blood touches.”
Literature
[1] Young, K. A., Hosseini, M., Mistry, J. J., Morganti, C., Mills, T. S., Cai, X., … & Trowbridge, J. J. (2025). Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nature Communications, 16(1), 3306.
[2] Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., … & Ebert, B. L. (2014). Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine, 371(26), 2488-2498.
[3] Hosseini, M., Voisin, V., Chegini, A., Varesi, A., Cathelin, S., Ayyathan, D. M., … & Chan, S. M. (2025). Metformin reduces the competitive advantage of Dnmt3a R878H HSPCs. Nature, 1-10.
