Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis
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...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57238-2 |
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| author | 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 Jennifer J. Trowbridge |
| author_facet | 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 Jennifer J. Trowbridge |
| author_sort | Kira A. Young |
| collection | DOAJ |
| description | 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 (Dnmt3a R878H/+), 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. |
| format | Article |
| id | doaj-art-744841855d7b4e4cac037805a0a306bf |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-744841855d7b4e4cac037805a0a306bf2025-08-20T02:06:36ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-57238-2Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesisKira A. Young0Mohsen Hosseini1Jayna J. Mistry2Claudia Morganti3Taylor S. Mills4Xiurong Cai5Brandon T. James6Griffin J. Nye7Natalie R. Fournier8Veronique Voisin9Ali Chegini10Aaron D. Schimmer11Gary D. Bader12Grace Egan13Marc R. Mansour14Grant A. Challen15Eric M. Pietras16Kelsey H. Fisher-Wellman17Keisuke Ito18Steven M. Chan19Jennifer J. Trowbridge20The Jackson LaboratoryPrincess Margaret Cancer Centre, University Health NetworkThe Jackson LaboratoryRuth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology, Oncology and Medicine, Montefiore Einstein Cancer Center, Albert Einstein College of MedicineDivision of Hematology, Department of Immunology and Microbiology, Anschutz Medical Campus, University of ColoradoThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryThe Jackson LaboratoryPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkUCL Cancer Institute, Department of Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child HealthDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Immunology and Microbiology, Anschutz Medical Campus, University of ColoradoEast Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Department of PhysiologyRuth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Departments of Cell Biology, Oncology and Medicine, Montefiore Einstein Cancer Center, Albert Einstein College of MedicinePrincess Margaret Cancer Centre, University Health NetworkThe Jackson LaboratoryAbstract 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 R878H/+), 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.https://doi.org/10.1038/s41467-025-57238-2 |
| spellingShingle | 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 Jennifer J. Trowbridge Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis Nature Communications |
| title | Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis |
| title_full | Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis |
| title_fullStr | Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis |
| title_full_unstemmed | Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis |
| title_short | Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis |
| title_sort | elevated mitochondrial membrane potential is a therapeutic vulnerability in dnmt3a mutant clonal hematopoiesis |
| url | https://doi.org/10.1038/s41467-025-57238-2 |
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