Supercharged Mitochondria Spark Aging-Related Blood Disorders
by Jennifer Trowbridge et al.
As we age, blood stem cells, which are the crucial source of new blood cells in the body, can accumulate genetic mutations. These mutations can confer a growth advantage to the cells, setting the stage for serious health conditions. Recent studies at The Jackson Laboratory (JAX) have revealed not only how these mutations fuel unchecked cell growth but also methods to inhibit this process.
The Role of Dnmt3a Mutation
Led by Jennifer Trowbridge, a professor and the Dattels Family Chair at JAX, the referenced research has demonstrated that a common aging-associated mutation in the Dnmt3a gene enhances the mitochondrial function in blood stem cells.
This mutation enables the cells to replicate more easily than their non-mutant counterparts, laying the groundwork for the development of clonal hematopoiesis, a condition significantly linked to an elevated risk of heart disease, blood cancers, and other serious illnesses.
Interestingly, clonal hematopoiesis develops silently as we age; more than 50% of those aged 80 and above are estimated to be affected by this condition. Mutated blood stem cells can produce inflammatory molecules that disrupt blood production and compromise the immune system.
“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.” - Dr. Jennifer Trowbridge
The Competitive Advantage of Mutated Stem Cells
In their investigation, the research team observed that middle-aged mice with the Dnmt3a mutation showed double the energy production of normal stem cells. This revelation indicates that the mutated stem cells possess turbocharged mitochondria, granting them a significant growth advantage.
Prior to this study, Dnmt3a was not recognized as a gene impacting metabolism and mitochondrial function. Research findings indicate that as these stem cells become increasingly reliant on their overactive mitochondria to fuel growth, the mitochondria may represent a crucial vulnerability in these cells.
Targeting Mitochondria in Treatment
Realizing the reliance of mutated stem cells on their mitochondria, the researchers tested the effects of two molecules, MitoQ and d-TPP, known to disrupt normal mitochondrial function and energy production.
Additionally, a separate study involving metformin—a medication traditionally used to manage type 2 diabetes—demonstrated its ability to diminish the competitive advantage of stem cells with the Dnmt3a mutation.
| Drug | Effect on Mutated Cells | Effect on Normal Cells |
|---|---|---|
| MitoQ | 50% of mutant cells deceased | No effect |
| d-TPP | Significant energy drop | No effect |
| Metformin | Reduced growth advantage | No effect |
Hope for Alleviating Human Disease
The treatment strategies with mitochondrial-targeting drugs have been validated in mouse models of clonal hematopoiesis, and human stem cells engineered to carry the DNMT3A gene mutation also showed positive results. These findings point towards a potential avenue for treating humans afflicted by age-related blood disorders, potentially preventing blood cancers and related conditions.
Nevertheless, further research remains essential to ascertain the efficacy of these drugs on other mutations associated with clonal hematopoiesis and understand their broader cellular effects.
Conclusion
The exploration of mitochondrial vulnerabilities in mutated blood stem cells not only illuminates new pathways for intervention against age-related blood disorders but also paves the way for innovative therapeutic strategies. This endeavor underscores the necessity of ongoing research aimed at targeting the fundamental mechanisms of aging to enhance health outcomes in the aging population.
References
Steven Chan, Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs, Nature (2025).
Retrieved from Medical Xpress.
Discussion