Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells

Aging leads to quantitative and qualitative changes in platelet (Plt) production, with increased risk for thrombosis and other adverse cardiovascular events. Recent reports showed that aging promotes the emergence of non-canonical (nc) megakaryocyte progenitors (MkPs) directly from hematopoietic stem cells (HSCs), leading to the production of hyperactive Plts. The higher engraftment potential of ncMkPs compared to both young and old canonical (c)MkPs, contrasts with the functional decline of old HSCs. Emerging reports suggest that mitochondrial function critically regulates lineage commitment and cellular functionality, but how mitochondrial activity affects aging megakaryopoiesis is unknown. Here, we demonstrate that aged MkPs sustain unique mitochondrial activity, characterized by higher mitochondrial membrane potential, higher ATP content, and lower ROS levels compared to their younger counterparts. This contrasts with the dysfunctional mitochondrial state observed in old HSCs, suggesting lineage-specific organelle adaptations upon aging. Notably, we observed that the elevated mitochondrial capacity in aged MkPs is driven selectively by the age-specific ncMkPs. Paradoxically, in vivo pharmacological enhancement of mitochondrial activity in old mice reduced in situ Plt production, but increased Plt reconstitution by transplanted HSCs. These discoveries link uniquely regulated mitochondrial capacity to the intrinsic properties of age-specific MkPs, raising the possibility of therapeutic targeting to prevent aging-induced megakaryopoiesis. HIGHLIGHTS Aging-specific MkPs have elevated mitochondrial capacity, the inverse of aged HSCs Mitochondrial enhancement differentially alters platelet counts in young and old mice Enhancement of mitochondrial capacity increases platelet repopulation by both young and old HSCs

• Publication year

  2025

• Venue

  bioRxiv

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2025.11.10.687744PMID 41292711PMCID 12642321
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A Rare Hematopoietic Stem Cell‐Derived Megakaryocyte Progenitor Accumulates via Enhanced Survival and Contributes to Exacerbated Thrombopoiesis Upon Aging

  2025influential reference
• Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling

  2024cited by this paper
• A metabolic atlas of blood cells in young and aged mice identifies uridine as a metabolite to rejuvenate aged hematopoietic stem cells

  2024cited by this paper
• SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.

  2024cited by this paper
• An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis.

  2024cited by this paper
• High mitochondrial DNA content is a key determinant of stemness, proliferation, cell migration, and cancer metastasis in vivo

  2024cited by this paper
• The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore

  2023cited by this paper
• Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems

  2023cited by this paper
• Mitochondria-targeted antioxidant MitoQ ameliorates ROS production and improves cell viability in cryopreserved buffalo fibroblasts.

  2023cited by this paper
• The fate of mitochondria during platelet activation

  2023cited by this paper
• Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells

  2021cited by this paper
• Mitochondrial Contributions to Hematopoietic Stem Cell Aging

  2021cited by this paper
• Mechanisms and rejuvenation strategies for aged hematopoietic stem cells

  2020cited by this paper
• The Evaluation of Mitochondrial Membrane Potential Using Fluorescent Dyes or a Membrane-Permeable Cation (TPP+) Electrode in Isolated Mitochondria and Intact Cells.

  2020cited by this paper
• Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function.

  2020cited by this paper
• Axicabtagene ciloleucel CD19 CAR-T cell therapy results in high rates of systemic and neurologic remissions in ten patients with refractory large B cell lymphoma including two with HIV and viral hepatitis

  2020cited by this paper
• Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition.

  2020cited by this paper
• Altered functions of platelets during aging.

  2019cited by this paper
• Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities.

  2019cited by this paper
• Aging of hematopoietic stem cells.

  2018cited by this paper
• Analysis of mtDNA/nDNA Ratio in Mice

  2017cited by this paper
• Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells.

  2017cited by this paper
• Measurement of Mitochondrial Mass by Flow Cytometry during Oxidative Stress.

  2017cited by this paper
• Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias

  2016cited by this paper
• Platelet function and ageing

  2016cited by this paper
• MitoSOX-Based Flow Cytometry for Detecting Mitochondrial ROS.

  2016cited by this paper
• Mitochondria: biological roles in platelet physiology and pathology.

  2014cited by this paper
• The role of mitochondria in aging.

  2013cited by this paper
• Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling.

  2012cited by this paper
• All hematopoietic cells develop from hematopoietic stem cells through Flk2/Flt3-positive progenitor cells.

  2011cited by this paper
• New insights into the role of mitochondria in aging: mitochondrial dynamics and more

  2010cited by this paper
• Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells

  2006cited by this paper
• Reactive Oxygen Species Control Hematopoietic Stem Cell-Niche Interaction through the Regulation of N-Cadherin.

  2006cited by this paper
• Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells

  2004cited by this paper
• MitoTracker Green labeling of mitochondrial proteins and their subsequent analysis by capillary electrophoresis with laser-induced fluorescence detection.

  2003cited by this paper

• No citing papers are available for this paper.