bims-mithem 2026-03-01 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2026–03–01
nine papers selected by
Tim van Tienhoven, Erasmus Medical Center

Hematopoietic stem cell aging promotes TET2 clonal hematopoiesis.
Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.
Tracking Human HSCs and MPPs in Mice Reveals Distinct Clonal Dynamics and Responses to Pre-transplant Conditioning.
The bone marrow microenvironment during homeostasis and after myeloablation.
Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
Neuropeptide Y deficiency in the bone marrow drives hematopoietic stem and progenitor cell aging.
Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
Energy Metabolic Regulatory Materials Promote Wound Healing in Senescent Environment.
Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.

Res Sq. 2026 Feb 09. pii: rs.3.rs-8704827. [Epub ahead of print]

Hematopoietic stem cell aging promotes TET2 clonal hematopoiesis.

James DeGregori, Marco De Dominici, Lamis Naddaf, Angelica Varesi, Andrew Goodspeed, Bridget Hoag, Vadym Zaberezhnyy, Johannes Menzel, Yang Liu, Stephanie Xie, Sheng Li.

Aging is strongly associated with the incidence of clonal hematopoiesis (CH) and myeloid malignancies. However, the role of aging in the clonal selection for CH mutations is not well understood. In a mouse model of CH, we observe that transplanted Tet2 KO hematopoietic stem cells (HSC) from old donor mice expand at a faster rate than young irrespective of the age of the recipient mice; that this acceleration is observed by middle age; and that it is primarily due to the aging-associated reduction in fitness of aged competitor non-mutant HSC. Mechanistically, in both mice and humans, we found that aged HSC exhibit enhanced activation of a RUNX1 transcriptional program and increased expression of ribosomal protein genes inducing a p53-mediated stress response, and that these changes are abrogated by Tet2/TET2 inactivation. Thus, aging creates the conditions that foster clonal expansion of Tet2, Runx1 and Trp53 mutant HSC promoting CH.

DOI: https://doi.org/10.21203/rs.3.rs-8704827/v1
Biomedicines. 2026 Jan 29. pii: 310. [Epub ahead of print]14(2):

Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.

Yijun Pan, Jiefu Zhu.

  Renal ischemia-reperfusion injury (IRI) is a leading trigger of acute kidney injury (AKI), a syndrome with high incidence and mortality worldwide. The kidney is among the most energy-demanding organs; its mitochondrial content is second only to the heart, rendering renal function highly contingent on mitochondrial integrity. Accumulating evidence places mitochondria at the center of IRI pathogenesis. During ischemia, ATP depletion, ionic disequilibrium, and Ca2+ overload set the stage for injury; upon reperfusion, a burst of mitochondrial reactive oxygen species (mtROS), collapse of the mitochondrial membrane potential (ΔΨm), aberrant opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA (mtDNA) damage, and release of mitochondrial damage-associated molecular patterns (mtDAMPs) further amplify inflammation and drive regulated cell-death programs. In recent years, the centrality of mitochondrial bioenergetics, quality control, and immune signaling in IRI-AKI has been increasingly recognized. Building on advances from the past five years, this review synthesizes mechanistic insights into mitochondrial dysfunction in renal IRI and surveys mitochondria-targeted therapeutic strategies-including antioxidant defenses, reinforcement of mitochondrial quality control (biogenesis, dynamics, mitophagy), and modulation of mtDAMP sensing-with the aim of informing future translational efforts in AKI.

Keywords:  AKI; antioxidant defenses; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitochondrial quality control; mtDAMPs; renal ischemia–reperfusion injury

DOI:  https://doi.org/10.3390/biomedicines14020310
bioRxiv. 2026 Feb 12. pii: 2026.02.10.705085. [Epub ahead of print]

Tracking Human HSCs and MPPs in Mice Reveals Distinct Clonal Dynamics and Responses to Pre-transplant Conditioning.

Mary Vergel Snodgrass, Jiya Eerdeng, Patrick Condie, Rong Lu.

Blood and immune cell regeneration is sustained by hematopoietic stem and progenitor cells (HSPCs), which form the therapeutic basis of bone marrow transplantation. While the functional hierarchy of mouse HSPC subsets is well characterized, the distinct roles of human HSPC populations remain less well defined, particularly at clonal resolution and in the context of transplantation conditioning. While clonal tracking in humans and non-human primates has significantly advanced our understanding of hematopoietic dynamics, prior studies predominantly focused on CD34 + cells, a heterogeneous population of HSPCs. Moreover, secondary transplantation is considered the gold standard for distinguishing hematopoietic stem cells (HSCs) from multipotent progenitors (MPPs) in mice, but it has not been effectively utilized to study human HSPC populations. To address this knowledge gap, we performed quantitative clonal tracking of purified human HSCs (hHSCs) and human MPPs (hMPPs) in NSGW41 mice across primary and secondary transplantation under no conditioning, busulfan, and irradiation. Consistent with prior studies, both hHSCs and hMPPs sustained long-term multilineage reconstitution and differed in engraftment rates. Our quantitative clonal analysis further revealed that hHSC clones generated more blood cells, initiated lymphoid production earlier, and exhibited more robust multilineage differentiation than hMPP clones. hHSC clones were also less sensitive to conditioning, maintaining stable lineage biases. Notably, busulfan and irradiation differentially affected the magnitude, lineage bias, and timing of hematopoietic reconstitution without altering engraftment. During secondary transplantation, hHSCs and hMPPs contributed comparably to hematopoietic reconstitution, but their overall output, particularly monocytes and T cells, was substantially reduced. In contrast to primary recipients, human chimerism of secondary recipients in the peripheral blood was diminished relative to the bone marrow and spleen, and more hHSPC clones contributed to hematopoiesis. Extramedullary hematopoiesis was observed in all secondary recipients, with comparable contributions from hHSC and hMPP clones. Overall, this study provides insights into the distinct functions of hHSCs and hMPPs, the influence of conditioning, and the inefficiency of human hematopoiesis through serial transplantation. These findings advance our understanding of human hematopoiesis and provide a framework for utilizing and optimizing experimental models, improving transplantation conditioning strategies, and informing the preclinical evaluation of HSC-based cell and gene therapies.

DOI: https://doi.org/10.64898/2026.02.10.705085
J Bone Miner Metab. 2026 Feb 25.

The bone marrow microenvironment during homeostasis and after myeloablation.

Shane Dong, Hiroyuki Hirakawa.

   BACKGROUND: Hematopoietic stem cells (HSCs) are the lifelong source of hematopoietic cells, maintained within the specialized microenvironment of the bone marrow. A central question remains regarding the mechanisms that regulate HSC maintenance. Functional studies have advanced our knowledge of the HSC niche, which consists of perivascular stromal, skeletal, and endothelial cells. Understanding the HSC niche is particularly important in the context of myeloablation which disrupts both the hematopoietic cells and their supporting microenvironment. As a clinical intervention, myeloablation followed by HSC transplantation is a well-established treatment option that has been shown to improve prognosis and increase survival in patients. These positive outcomes result from the reconstitution of the hematopoietic system by transplanted HSCs with the support of the regenerated microenvironment.
OBJECTIVE: Recent studies have made significant progress in understanding the plasticity of the bone marrow microenvironment. This review provides an overview of recent findings on the HSC niche during homeostasis and after myeloablative stress.
CONCLUSION: Despite the advances made, it is still unclear how the bone marrow microenvironment adjusts and regenerates after stress. Further advances in understanding HSC niche regeneration could have important implications for patient care.

Keywords:  Bone marrow microenvironment; Hematopoietic regeneration; Hematopoietic stem cell; Myeloablation

DOI:  https://doi.org/10.1007/s00774-026-01707-1
Can J Cardiol. 2026 Feb 23. pii: S0828-282X(26)00152-2. [Epub ahead of print]

Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.

Ryan C Falconer, Emily A Day.

  Macrophages are key cells of the innate immune system. Within the cardiovascular system, macrophages exhibit marked phenotypic plasticity, enabling them to sense local cues and regulate vascular inflammation, myocardial injury, and tissue remodeling. Mitochondria serve as multifunctional organelles in macrophages, integrating cellular metabolism with the production of immunogenic signals that shape inflammatory responses. In cardiovascular disease (CVD), mitochondrial dysfunction in macrophages drives maladaptive inflammatory responses that when unresolved, lead to chronic inflammation and tissue injury underlying adverse cardiovascular outcomes. To preserve mitochondrial integrity under diverse conditions, cells engage an interconnected network of mitochondrial quality control (MQC) mechanisms, namely mitochondrial biogenesis, maintenance of mitochondrial DNA (mtDNA), remodelling by fission and fusion, mitophagy, and the mitochondrial unfolded protein response. This review examines how these MQC systems govern macrophage polarization, inflammatory signalling, and survival in CVD, focusing on atherosclerosis, myocardial infarction, and heart failure. We discuss evidence demonstrating that the dysregulation of these mechanisms in macrophages, contributes to cardiovascular impairment, with particular emphasis on how dysregulated mitochondrial dynamics, heightened mitochondrial oxidative stress, and mtDNA release converge to amplify inflammation in CVD. We further highlight clinical evidence suggesting that current therapies, such as statins, SGLT2 inhibitors, and GLP-1 receptor agonists enhance macrophage MQC to alleviate stress, improve metabolic function, and dampen inflammation, which may contribute to their cardiovascular benefit. By examining the role of MQC in macrophages within the cardiovascular system, this review establishes the mechanisms governing mitochondrial homeostasis and dysfunction as a critical immunometabolic axis and potential therapeutic avenue underlying cardiovascular disease.

Keywords:  Immunometabolism; Macrophages; Mitochondria; Mitochondrial Quality Control; cGAS-STING

DOI:  https://doi.org/10.1016/j.cjca.2026.02.034
bioRxiv. 2026 Feb 20. pii: 2026.02.20.706987. [Epub ahead of print]

Neuropeptide Y deficiency in the bone marrow drives hematopoietic stem and progenitor cell aging.

Dinisha Kamble, James P Ropa, Malgorzata M Kamocka, Yan Qi, Nick Imperiale, Pratibha Singh.

Aging-related blood disorders are linked to defects in the regenerative and multilineage differentiation ability of hematopoietic stem and progenitor cells (HSPCs). While remodeling of the bone marrow (BM) microenvironment where HSPCs reside is known to contribute to these age-associated defects, the underlying factors and mechanisms remain poorly defined. Here, we discovered that the age-related decline of the neurotransmitter neuropeptide Y (NPY) in the BM is a critical driver of HSPC dysfunction. Using mouse models, we demonstrated that NPY levels decrease in the BM with age, and that genetic NPY overexpression or exogenous NPY administration in old mice substantially reverses aging-associated phenotypic and functional defects in HSPCs. Transcriptome analysis revealed that NPY supplementation in old mice restores aging-disrupted molecular pathways in their HSCs, including oxidative stress responses, myeloid differentiation, stemness, mitochondrial activity, and RhoA signaling. However, NPY genetic loss in young mice led to a decline in HSCs regenerative capacity and increased oxidative stress. Importantly, NPY levels also decline in elderly humans, and ex vivo treatment of human BM-derived HSPCs with NPY enhances their in vivo repopulating capacity. These results suggest that NPY supplementation or preservation of NPY-producing nerve fibers could be a therapeutic strategy to rejuvenate aged HSC function.

DOI: https://doi.org/10.64898/2026.02.20.706987
Cells. 2026 Feb 20. pii: 372. [Epub ahead of print]15(4):

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.

Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton, Michela Casella.

  Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control-encompassing fusion-fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis-compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS-STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.

Keywords:  cardiovascular disease; inflammation; mitochondrial dysfunction; mitochondrial quality control; mitochondrial signaling; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/cells15040372
Prog Mol Subcell Biol. 2026 ;63 1-45

Energy Metabolic Regulatory Materials Promote Wound Healing in Senescent Environment.

Xuetong Wang, Tingbin Zhang, Huan Zhou, Lei Yang.

  Chronic wounds, pathological states failing to heal promptly, are especially prevalent among the elderly. This impaired healing in the senescent tissue is predominately attributed to the accumulation of senescent cells and a concomitant decline in energy metabolism, ultimately leading to functional impairment. Existing clinical practices-including debridement, hyperbaric oxygen, antibiotics, and wound dressings-cannot fundamentally resolve this cellular decline. In this context, advanced biomaterials designed to enhance cellular energy metabolism emerge as a viable strategy. This chapter details strategies by which biomaterials enhance skin wound healing in aging environments by modulating energy metabolism. It explains that delayed healing primarily stems from age-associated metabolic and mitochondrial dysregulation, which compromises cellular repair functions. Furthermore, it reviews advanced biomaterial-based approaches that promote healing by delivering metabolites, restoring mitochondrial function, and indirectly modulating stem cells. By targeting energy metabolism to reverse the low-energy state of aged skin, these approaches fundamentally address cellular functional decline and actively foster tissue regeneration. Therefore, this chapter outlines design principles for energy metabolism-modulating biomaterials to aid wound healing in aged skin and highlights recent advances in this field.

Keywords:  Advanced biomaterials; Drug delivery; Energy metabolism; Mitochondria; Nanotechnology; Senescence; Stem cells; Wound healing

DOI:  https://doi.org/10.1007/978-3-032-17771-1_1
bioRxiv. 2026 Feb 18. pii: 2026.02.12.705660. [Epub ahead of print]

Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.

Teng Gao, Chen Weng, Isaac Johnson, Michael Poeschla, Jonas Gudera, Emily King, Christopher Rouya, Adriana Donovan, Lauren Bourke, Ying Shao, Eladio Marquez, Rahul Tyagi, Leonard I Zon, Jonathan S Weissman, Vijay G Sankaran.

Somatic mutations in mitochondrial DNA (mtDNA) provide natural barcodes that enable engineering-free lineage tracing in human tissues, but the complex dynamics of mtDNA inheritance across cell divisions and incomplete sampling of mtDNA introduce uncertainty in reconstructed lineages. Here, we present MitoDrift, a probabilistic framework that integrates Wright-Fisher drift dynamics with sparse single-cell measurements to produce confidence-refined lineage trees enriched for accurate clonal relationships. Validation with gold-standard lentiviral barcoding and whole-genome sequencing demonstrates that MitoDrift outperforms existing tree reconstruction methods in precision while maintaining high clonal recovery, enabling robust analyses linking lineage to cell state. Applying MitoDrift to human hematopoiesis reveals an age-associated decline in clonal diversity with differential impact across cell types and identifies heritable regulatory programs in hematopoietic stem cells in vivo, linking AP-1/stress-associated programs to clonal expansions. In multiple myeloma, MitoDrift captures therapy-associated clonal remodeling undetectable by copy number analysis, revealing phenotypic transitions and linking gene regulatory programs to differential drug sensitivity. Collectively, MitoDrift enables high-precision lineage tracing at scale and establishes quantitative lineage-state analysis in primary human tissues, linking clonal history to transcriptional and epigenetic programs in tissue homeostasis, aging, and disease.

DOI: https://doi.org/10.64898/2026.02.12.705660