bims-mithem Biomed News
on Mitochondria in Hematopoiesis
Issue of 2026–01–25
eleven papers selected by
Tim van Tienhoven, Erasmus Medical Center
  1. Rora Regulates Hematopoietic Stem Cell Phenotypes and Progression of Chronic Myelogenous Leukemia.
  2. Ligature-induced periodontitis promotes Dnmt3a R878H-driven clonal hematopoiesis.
  3. Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting.
  4. Mast cells in the bone marrow microenvironment.
  5. Impact of Toll/Interleukin-1 Receptor Domain Protein C on Mesenchymal Stem Cells Mitochondrial Protein Expression: A Proteomic Study.
  6. TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
  7. Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
  8. Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.
  9. Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
  10. Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.
  11. Cellular senescence as a therapeutic target for aging intervention.
  1. Am J Pathol. 2026 Jan 15. pii: S0002-9440(26)00004-0. [Epub ahead of print]
    Rora Regulates Hematopoietic Stem Cell Phenotypes and Progression of Chronic Myelogenous Leukemia.
    Ning Li, Yunyu Feng, Nan Wang, Wei He, Hongjian Li, Xue Cui, Bochuan Wang, Runkuan Qin, Huandi Qiu, Qiang Qiu, Li Zheng, Yuanyuan Sun, Linye He, Cong Pan, Anping Su, Zhihui Li, Yiguo Hu.
      Hematopoietic stem cell (HSC) aging leads to hematological dysfunction and diseases, but the regulatory factors involved remain incompletely characterized. In this study, HasCATs model was developed to identify transcription factors (TFs) that resist HSC aging. This approach revealed RORA as a key Aging-Negative-Associated TF. Rora deletion in HSCs caused aged phenomes and functionally impaired their reconstitutive capacity. Additionally, Rora deficiency impaired leukemia stem cells (LSC) proliferation and prevented Chronic Myelogenous Leukemia (CML). These findings establish RORA as a critical regulator in maintaining HSC function and provide insights into its therapeutic potential in hematological disorders.
    Keywords:  Aging; DNA damage; RORA; hematopoietic stem cells (HSCs); transcription factors
    DOI:  https://doi.org/10.1016/j.ajpath.2025.12.010
  2. Haematologica. 2026 Jan 22.
    Ligature-induced periodontitis promotes Dnmt3a R878H-driven clonal hematopoiesis.
    Qiao Yuan, Min Liao, Ziyao Zhuang, Chenyan Huang, Rixin Chen, Yuxian Song, Yu Wu, Peihui Zou, Lili Li, Hua Nie, Miaomiao Zhang, Shiyuan Song, Yanfen Li, Fuhua Yan.
      Characterized by somatic mutations (e.g., DNMT3A) in blood cells, clonal hematopoiesis (CH) is an age-related process wherein mutated hematopoietic stem and progenitor cells (HSPCs) expand. This expansion thereby increases the risk of all-cause mortality, myeloid hematologic malignancies and other nonmalignant disorders, yet the risk factors that contribute to CH are still largely unknown. Periodontitis induces low-grade systemic inflammation and affects an estimated 62% of dentate adults globally, which may influence CH-associated pathologies. Periodontitis was modeled by bilateral maxillary second molar ligation in mice; CH was established using hematopoietic-specific Dnmt3a R878H mutant mice. Periodontal bone destruction was assessed via micro-computed tomography and H/E-staining. Changes in bone marrow HSPCs, peripheral blood cells, and gingival immune cells were analyzed by flow cytometry. Key molecular mediators were identified through transcriptomic sequencing of sorted gingival myeloid cells and serum cytokine arrays. Results showed that ligature-induced periodontitis (LIP) promoted Dnmt3a R878H-driven clonal hematopoiesis, manifested as a myeloid-biased phenotype characterized by increased myeloid cells in the gingiva and peripheral blood. The selective enrichment of the Dnmt3a R878H clones during LIP is primarily because Dnmt3a R878H HSCs exhibit enhanced resistance and maintain competitive advantages within inflammatory microenvironments. Transcriptomic analysis revealed upregulation of Ccl17 in gingival R878H myeloid cells, which was corroborated by elevated serum and bone marrow levels of CCL17. The CCL17 upregulation drove myeloid cells recruitment to the gingiva, exacerbating periodontitis while simultaneously reinforcing Dnmt3a R878H HSC expansion. This study highlights the necessity of controlling local chronic inflammation, such as periodontitis, in the clinical management of CH.
    DOI:  https://doi.org/10.3324/haematol.2025.288827
  3. Front Oncol. 2025 ;15 1736487
    Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting.
    Wei Huang, Wei Sun, Zhiyuan Yang, Yiwen Li, Ziliang Wang.
      Cisplatin remains a cornerstone of chemotherapy for numerous cancers, despite the persistent challenges of toxicity and the development of drug resistance. Therefore, a deeper understanding of the mechanisms behind cisplatin resistance and the development of strategies to counter it are of critical importance. This review systematically examines the pivotal role of mitochondrial dynamics in cisplatin resistance and discusses emerging therapeutic strategies that target these processes. Mitochondrial dynamics regulate the structure and function of the mitochondrial network through a balance of fusion and fission. Dysregulation of this process directly contributes to cisplatin resistance by maintaining cellular energy homeostasis, inhibiting apoptosis, and enhancing oxidative phosphorylation (OXPHOS). Furthermore, mitophagy, metabolic reprogramming, and the tumor immune microenvironment converge on mitochondrial dynamics to drive the acquisition of drug resistance. Consequently, targeting mitochondrial dynamics presents a promising approach to overcome cisplatin resistance. Potential strategies include restoring the balance of fusion and fission, intervening in mitophagy, disrupting OXPHOS metabolism, and developing mitochondrial-targeted nanodrug delivery systems. However, despite this promising outlook, significant challenges remain, including the heterogeneity of resistance mechanisms, a lack of reliable biomarkers, and the need for selective targeting to minimize off-target effects.
    Keywords:  cisplatin resistance; immune microenvironment; metabolic reprogramming; mitochondrial dynamics; mitophagy; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2025.1736487
  4. Front Immunol. 2025 ;16 1738487
    Mast cells in the bone marrow microenvironment.
    Domenico Ribatti.
      The bone marrow microenvironment provides the necessary signals for the development from hematopoietic stem cells into mast cell precursors. Once released in the bloodstream, mast cells quickly migrate to peripheral tissues where they complete their differentiation. Mast cells are located at the interface with the external environment, therefore are among the first cell types that can get in contact with pathogens. Mast cells are found in every tissue, most abundantly near barriers where they exert the role of immune sentinels during both acute and chronic inflammation. Mast cells are known for their effects when eliciting immediate hypersensitivity reactions. However, they are involved in numerous other physiological and pathological conditions such as those that occur in bone marrow microenvironment, as has been discussed in this article.
    Keywords:  angiogenesis; bone marrow; fibrosis; mast cells; tumor progression
    DOI:  https://doi.org/10.3389/fimmu.2025.1738487
  5. Curr Mol Med. 2026 Jan 13.
    Impact of Toll/Interleukin-1 Receptor Domain Protein C on Mesenchymal Stem Cells Mitochondrial Protein Expression: A Proteomic Study.
    Yameng Wang, Jiaqi Fang, Dongyang Guo, Liang Xia.
       INTRODUCTION: Stem cells play a pivotal role in immunomodulation and tissue repair, and their functions can be influenced by TLR signaling. The Toll/interleukin-1 receptor domain-containing protein C (TcpC), secreted by Uropathogenic Escherichia coli, can inhibit host immunity by interfering with TLR pathways. As mitochondria are crucial for stem cell function, there may be links between TcpC and mitochondrial homeostasis.
    METHODS: We isolated MSC mitochondria using magnetic beads coated with a monoclonal antibody against the outer mitochondrial membrane protein OMP25 and conducted a proteomic study to examine the MSC mitochondrial proteome with or without TcpC. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and proteinprotein interaction (PPI) network analysis, were employed.
    RESULTS: A total of 33 proteins with significant changes in abundance were identified: 4 increased in abundance, including glycolytic enzymes (Pkm [FC=1.6599, p=0.0217]) and stress response proteins (Ywhaq [FC=1.4666, p=0.04502]); and 29 decreased, mainly related to mitochondrial oxidative phosphorylation (e.g., Atp5f1e [FC=0.001, p=0.00120], Ndufa11 [FC=0.001, p=0.00674]) and protein quality control (e.g., Grpel1 [FC=0.46663, p=0.02083], Hspa9 [FC=0.48089, p=0.0435], Pitrm1 [FC=0.12764, p=0.01388]).
    DISCUSSION: The possible effects of TcpC on the MSC mitochondrial proteome are reported here for the first time. This information provides a clearer understanding of MSCs in the context of infectious disease and offers a scientific basis for future stem cell therapy research.
    CONCLUSION: TCP-C intervention leads to a series of differentially expressed proteins in MSC mitochondria, which are involved in several functional clusters, including oxidative phosphorylation, respiratory electron transport, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, branched-chain amino acid catabolism, and cristae formation.
    Keywords:  Mesenchymal stem cells; Mitochondria; TCPC; oxidative phosphorylation; protein quality control.; proteomics
    DOI:  https://doi.org/10.2174/0115665240411988251128121911
  6. FASEB J. 2026 Jan 31. 40(2): e71467
    TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
    Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.
      The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
    Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria
    DOI:  https://doi.org/10.1096/fj.202503182RR
  7. Aging Cell. 2026 Feb;25(2): e70386
    Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
    Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Charles L Hoppel, Cristal M Hill, Christopher D Morrison, Christopher L Axelrod, Gangarao Davuluri, John P Kirwan.
      Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK-ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS-STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.
    Keywords:  bioenergetics; fission; fusion; heart; mitochondria; obesity; quality control
    DOI:  https://doi.org/10.1111/acel.70386
  8. Haematologica. 2026 Jan 22.
    Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.
    Xiaoxi Yang, Sandy Lee, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan.
      Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and expansion of neoplastic hematopoietic stem cells (HSCs). Megakaryocytes (MKs) not only regulate HSC function but also shape immune responses within the marrow niche. Using an aging murine model of MPN with MK-restricted JAK2V617F expression, we investigated the immunomodulatory roles of mutant MKs. Compared to wild-type MKs, aged mutant MKs exhibit enhanced antigen uptake and MHC I presentation, secretion of pro-inflammatory cytokines (PF4, TGFβ, IL-1β), and induction of T cell dysregulation in the marrow niche. In chimeric murine models with co-existing wild-type and JAK2V617F mutant hematopoietic cells, enhanced MK immune activity correlates with mutant cell expansion and MPN development. Single-cell RNA sequencing revealed that aging amplifies JAK2V617F MK-driven immune remodeling. Notably, aged mutant MKs showed marked upregulation of LINE-1 (long-interspersed element-1) retrotransposon transcripts alongside elevated innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), implicating retrotransposon activity in niche inflammation. In human MPN marrow, immunohistochemistry detected LINE-1-encoded protein ORF1p in MKs from 12 of 13 MPN patients, but not in orthopedic controls (n=5). These findings identify MKs as active immune regulators in MPNs, with JAK2V617F mutation and aging synergizing to reprogram MKs into inflammatory, immunemodulatory niche cells. LINE-1 activation emerges as a potential driver of chronic marrow inflammation and a targetable mechanism in clonal hematopoiesis and MPN progression.
    DOI:  https://doi.org/10.3324/haematol.2025.288948
  9. Adv Sci (Weinh). 2026 Jan 22. e23368
    Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
    Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.
      Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.
    Keywords:  chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics
    DOI:  https://doi.org/10.1002/advs.202523368
  10. Aging Cell. 2026 Feb;25(2): e70387
    Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.
    Howard J Phang, Jaclyn Bergstrom, Benjamin Keri, Stephanie R Heimler, Stephen Dozier, Lina M Scandalis, David Wing, Daniel Moreno, Nina N Sun, Anthony J A Molina.
      Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20-80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.
    DOI:  https://doi.org/10.1111/acel.70387
  11. Biomed J. 2026 Jan 17. pii: S2319-4170(26)00004-1. [Epub ahead of print] 100948
    Cellular senescence as a therapeutic target for aging intervention.
    Youkun Bi, Guangju Ji.
      Cellular senescence is a stress-induced cellular state that contributes to tissue dysfunction, chronic inflammation, and a broad range of aging-associated pathologies. The accumulation of senescent cells (SnCs) disrupt normal tissue function, positioning them as drivers of pathological decline and therapeutic targets for aging intervention. Accordingly, multiple senescence-targeted strategies have been developed, including senolytics, senomorphics, senescence immunotherapy, and restoration-oriented interventions. These approaches aim to mitigate senescence-driven pathology by eliminating senescent cells, modulating their secretory activity, or restoring cellular function. Ongoing advancements will require precise stratification of senescent states, careful assessment of long-term safety, and the integration of optimized delivery systems for targeted therapeutic outcomes.
    Keywords:  Cellular senescence; Restoration-oriented interventions; Senescence immunotherapy; Senolytics; Senomorphics
    DOI:  https://doi.org/10.1016/j.bj.2026.100948
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