Document Type
Article
Publication Date
4-16-2025
Original Citation
Young K,
Hosseini M,
Mistry J,
Morganti C,
Mills T,
Cai X,
James B,
Nye G,
Fournier N,
Voisin V,
Chegini A,
Schimmer A,
Bader G,
Egan G,
Mansour M,
Challen G,
Pietras E,
Fisher-Wellman K,
Ito K,
Chan S,
Trowbridge JJ.
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nat Commun. 2025;16(1):3306.
Keywords
JGM, SS1, Animals, DNA Methyltransferase 3A, Hematopoietic Stem Cells, DNA (Cytosine-5-)-Methyltransferases, Mice, Membrane Potential, Mitochondrial, Humans, Mitochondria, Clonal Hematopoiesis, Oxidative Phosphorylation, Mutation, Apoptosis, DNA Methylation, Mice, Inbred C57BL, Aging, Organophosphorus Compounds, Male, Hematopoiesis
JAX Source
Nat Commun. 2025;16(1):3306.
ISSN
2041-1723
PMID
40240771
DOI
https://doi.org/10.1038/s41467-025-57238-2
Grant
This work was supported by National Institutes of Health grants R01DK118072 (J.J.T.), R56DK118072 (J.J.T.), R01AG069010 (J.J.T.), U01AG077925 (J.J.T.), P30CA034196 (J.J.T.), and grants from the Edward P. Evans Foundation (J.J.T. and G.A.C.). Addi- tional support was received from the Leukemia & Lymphoma Society (J.J.T., K.I., J.J.M.)
Abstract
The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.