Dnmt3a mutation enhances mitochondrial function in blood stem cells, leading to clonal expansion and increased disease risk
The Jackson Laboratory’s recent study, published on April 16, 2025, in Nature Communications, uncovers how a common age-related mutation in the Dnmt3a gene enhances mitochondrial function in blood stem cells, leading to clonal hematopoiesis—a condition that increases the risk of heart disease, blood cancers, and other illnesses.
Key Findings
- Dnmt3a Mutation and Mitochondrial Enhancement: The Dnmt3a mutation boosts mitochondrial energy production in blood stem cells, granting them a self-renewal advantage.
- Development of Clonal Hematopoiesis: This advantage leads to clonal hematopoiesis, where mutated stem cells dominate, increasing the risk of various diseases.
- Prevalence in Aging Population: Clonal hematopoiesis is common in the elderly, affecting over half of individuals aged 80 and above.
- Inflammatory Impact: Mutated stem cells produce inflammatory molecules that disrupt blood production and weaken the immune system.
- Therapeutic Potential: The study suggests that targeting the enhanced mitochondrial function could be a strategy to prevent or treat clonal hematopoiesis.
These findings show that Dnmt3a-mutated cells rely on enhanced mitochondrial function to dominate,” said senior author Dr. Jennifer Trowbridge. “Targeting this metabolic vulnerability could be a promising strategy to prevent or treat clonal hematopoiesis and its downstream effects.
Marvin Edeas, INSERM, University of Paris, co-organiser of the Targeting Longevity & Mitochondria congress, stated, “This discovery brings new insight into how the aging process is closely linked to energy production in our cells, especially through mitochondria, the cell’s powerhouses. When mitochondria become overactive due to certain mutations, they give some cells an unfair growth advantage, which can lead to harmful conditions like clonal hematopoiesis and increase the risk of diseases such as blood cancer or heart problems. By targeting and calming this mitochondrial overactivity, we may be able to stop these abnormal cells from expanding and protect against age-related diseases. This could represent an important step toward healthier aging.
In a separate publication in Nature published April 16th, Dr. Jennifer Trowbridge provided preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.
What is DNMT3A?
- It is de novo methyltransferase, meaning it can establish new methylation patterns during development and in adult tissues.
- It plays a crucial role in stem cell differentiation, development, and maintaining genomic stability.
- Mutations in Dnmt3a are commonly found in clonal hematopoiesis, leukemias, and other age-related diseases.
- Recent research shows these mutations can alter mitochondrial function, giving mutant cells a growth advantage.
