Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis
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 (Dnmt3a<sup>R878H/+</sup>), 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.
Authors
- Natalie R Fournier
- Grace Egan (ORCID: https://orcid.org/0000-0002-4036-8403)
- Jayna J. Mistry
- Taylor Mills (ORCID: https://orcid.org/0000-0003-0030-4242)
- Gary D. Bader (ORCID: https://orcid.org/0000-0003-0185-8861)
- Véronique Voisin (ORCID: https://orcid.org/0000-0002-3405-9532)
- Eric M. Pietras (ORCID: https://orcid.org/0000-0002-7339-8828)
- Keisuke Ito (ORCID: https://orcid.org/0000-0002-6702-9735)
- Mohsen Hosseini (ORCID: https://orcid.org/0000-0002-1686-8512)
- Xiurong Cai (ORCID: https://orcid.org/0000-0002-6937-3708)
- Briscoe James (ORCID: https://orcid.org/0000-0002-1824-747X)
- Aaron David Schimmer (ORCID: https://orcid.org/0000-0003-4023-3899)
- Griffin J. Nye
- Kelsey H. Fisher‐Wellman (ORCID: https://orcid.org/0000-0002-0300-829X)
- Kira Young (ORCID: https://orcid.org/0000-0002-1598-9793)
- Steven M. Chan (ORCID: https://orcid.org/0000-0002-4354-0731)
- Grant Anthony Challen (ORCID: https://orcid.org/0000-0003-4669-8814)
- Marc R. Mansour (ORCID: https://orcid.org/0000-0001-6835-3791)
- Jennifer J. Trowbridge (ORCID: https://orcid.org/0000-0002-7636-9504)
- Ali Chegini
- Claudia Morganti
Institutions
- University of North Carolina at Chapel Hill (US)
- Albert Einstein College of Medicine (US)
- University Health Network (CA)
- University of Toronto (CA)
- East Carolina University (US)
- Washington University in St. Louis (US)
- Hospital for Sick Children (CA)
- Princess Margaret Cancer Centre (CA)
- Occupational Cancer Research Centre (CA)
- Jackson Laboratory (US)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s41467-025-57238-2
- Citations
- 16
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 28.32
Funders
- National Science Foundation
- Leukemia and Lymphoma Society
- Edward P. Evans Foundation
- National Institutes of Health
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases