Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis

Kira A. Young, Mohsen Hosseini, Jayna J. Mistry, Claudia Morganti, Taylor S. Mills, Xiurong Cai, Brandon T. James, Griffin J. Nye, Natalie R. Fournier, Veronique Voisin, Ali Chegini, Aaron D. Schimmer, Gary D. Bader, Grace Egan, Marc R. Mansour, Grant A. Challen, Eric M. Pietras, Kelsey H. Fisher-Wellman, Keisuke Ito, Steven M. Chan and Jennifer J. Trowbridge ()
Additional contact information
Kira A. Young: The Jackson Laboratory
Mohsen Hosseini: University Health Network
Jayna J. Mistry: The Jackson Laboratory
Claudia Morganti: Albert Einstein College of Medicine
Taylor S. Mills: University of Colorado
Xiurong Cai: The Jackson Laboratory
Brandon T. James: The Jackson Laboratory
Griffin J. Nye: The Jackson Laboratory
Natalie R. Fournier: The Jackson Laboratory
Veronique Voisin: University Health Network
Ali Chegini: University Health Network
Aaron D. Schimmer: University Health Network
Gary D. Bader: University Health Network
Grace Egan: University Health Network
Marc R. Mansour: UCL Great Ormond Street Institute of Child Health
Grant A. Challen: Washington University School of Medicine
Eric M. Pietras: University of Colorado
Kelsey H. Fisher-Wellman: Department of Physiology
Keisuke Ito: Albert Einstein College of Medicine
Steven M. Chan: University Health Network
Jennifer J. Trowbridge: The Jackson Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57238-2

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