bims-mithem 2025-09-07 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2025–09–07
ten papers selected by
Tim van Tienhoven, Erasmus Medical Center

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
Mitochondrial Quality Control.
Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.
Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review).
Molecular mechanisms of mitochondrial quality control.
The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.
Innovative strategies for mitochondrial dysfunction in myeloproliferative neoplasms a step toward precision medicine.
Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.
The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.
Iron overload promotes myeloid differentiation of normal hematopoietic stem cells and educates macrophage mediated immunosuppression in acute myeloid leukemia.

EMBO Rep. 2025 Aug 29.

Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.

Lin Luo, Ana Victoria Lechuga-Vieco, Clara Sattentau, Mariana Borsa, Anna Katharina Simon.

  Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.

Keywords:  Asymmetric Cell Division; Mitochondrial Metabolism; Mitochondrial Transfer; Mitophagy; T Cell Ageing

DOI:  https://doi.org/10.1038/s44319-025-00536-z
Adv Exp Med Biol. 2025 ;1478 51-60

Mitochondrial Quality Control.

Yuntian Guan, Zhen Yan.

  Mitochondria, the power plants of cells, are essential for various cellular functions. In skeletal muscle, mitochondria form a network, called mitochondrial reticulum, which fuels muscle contractile and metabolic functions. The high degree of structure-to-function specialization of mitochondria in skeletal muscle implies that it is closely gauged and regulated to maintain energy production capacity to match the functional demands. The processes that regulate the overall structure and function of mitochondrial reticulum are collectively referred to as mitochondrial quality control. Mitochondrial quality control consists of mitochondrial biogenesis, dynamics (i.e., fission and fusion), and selective degradation via proteolysis and mitophagy. In this chapter, we will discuss different aspects of contemporary understanding of mitochondrial quality control, their respective mechanisms, and their adaptability to exercise training.

Keywords:  Adaptation; Exercise; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial reticulum; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1007/978-3-031-88361-3_3
J Transl Int Med. 2025 Jun;13(3): 211-240

Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.

Miao Zhang, Tong Zhang, Rongjun Zou, Kunyang He, Ru Huang, Jingrui Feng, Jinlin Hu, Teng Ge, Xiaoping Fan, Hao Zhou, Yang Chen.

  Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases.

Keywords:  fusion; mitochondrial death; mitochondrial fission; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1515/jtim-2025-0030
Int J Mol Med. 2025 Nov;pii: 183. [Epub ahead of print]56(5):

Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review).

Gong Qing, Chao Huang, Jixiang Pei, Bo Peng.

  Doxorubicin (DOX)‑induced cardiotoxicity (DIC) remains a critical challenge in cancer therapy, significantly limiting its use in clinical practice. The underlying mechanisms involve disruptions in cardiac metabolism and mitochondrial dysfunction. The heart relies on mitochondrial oxidative phosphorylation to produce ATP, which is essential for maintaining both contraction and relaxation. DOX disrupts glucose metabolism and fatty acid oxidation, resulting in energy shortages and excessive production of reactive oxygen species (ROS). These ROS contribute to mitochondrial damage, organelle malfunction and eventually cardiomyocyte death. This review describes the pathophysiological aspects of DIC, emphasising the molecular mechanisms underlying mitochondrial dysfunction and metabolic dysregulation in the heart during DIC progression. Additionally, the potential diagnostics, therapeutic interventions and drugs targeting metabolic pathways are summarised, focusing on metabolic modulation, combining non‑pharmacological therapies, such as exercise, fasting and mitochondrial transplantation, and approaches to enhance mitochondrial quality control, offering promising theoretical insights and practical strategies for DIC prevention and management.

Keywords:  cardiotoxicity; doxorubicin; metabolism; mitochondrial dysfunction

DOI:  https://doi.org/10.3892/ijmm.2025.5624
Transl Neurodegener. 2025 Sep 01. 14(1): 45

Molecular mechanisms of mitochondrial quality control.

Wensheng Li, Yuran Gui, Cuiping Guo, Yuting Huang, Yi Liu, Xuan Yu, Huiliang Zhang, Jianzhi Wang, Rong Liu, Yacoubou Abdoul Razak Mahaman, Qiuhong Duan, Xiaochuan Wang.

  Mitochondria produce adenosine triphosphate (ATP), the main source of cellular energy. To maintain normal function, cells rely on a complex mitochondrial quality control (MQC) system that regulates mitochondrial homeostasis, including mitochondrial dynamics, mitochondrial dynamic localization, mitochondrial biogenesis, clearance of damaged mitochondria, oxygen radical scavenging, and mitochondrial protein quality control. The MQC system also involves coordination of other organelles, such as the endoplasmic reticulum, lysosomes, and peroxisomes. In this review, we discuss various ways by which the MQC system maintains mitochondrial homeostasis, highlight the relationships between these pathways, and characterize the life cycle of individual mitochondria under the MQC system.

Keywords:  Evidence-based therapies; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Mitochondrial quality control

DOI:  https://doi.org/10.1186/s40035-025-00505-5
Leuk Res Rep. 2025 ;24 100537

The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.

Sona Rezaei, Mohammad Mohammadzadeh-Vardin, Keyvan Amirshahrokhi, Mojtaba Amani.

  Acute myeloid leukemia (AML) often relapses post-chemotherapy due to leukemia stem cells (LSCs), which rely on mitochondria for energy, ROS regulation, and apoptosis. Targeting mitochondrial pathways may overcome LSC resistance. This study evaluated Cytarabine (Ara-C), 2-Deoxy-d-Glucose (2-DG), and their combination on AML-derived KG1-a cells using MTT assays, showing reduced viability with combined treatment. The Magnetic sorting isolated CD34+ (stem-like) and CD34- cells. Flow cytometry revealed increased ROS and decreased mitochondrial membrane potential (MMP) in KG1-a and CD34+ cells with 2-DG and Ara-C, suggesting a promising strategy to target resistant LSCs in AML therapy.

Keywords:  CD34+ stem-like cells; Cytarabine, 2-deoxy-D-glucose; Mitochondrial membrane potential; Reactive oxygen specious

DOI:  https://doi.org/10.1016/j.lrr.2025.100537
Ann Med Surg (Lond). 2025 Sep;87(9): 5557-5568

Innovative strategies for mitochondrial dysfunction in myeloproliferative neoplasms a step toward precision medicine.

Shinto Bosco, Shreya Singh Beniwal, Samid Soeb Munshi, Daniela Castro Calderón, Yujin Jeong, Alyanna Cabe Cacas, Sandeep Kumar, Pedro Henrique Serra Carvalho Dos Santos, Saif Syed, Ayush Dwivedi, Mahmoud Einieh.

  Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells characterized by aberrant proliferation of myeloid lineages, driven primarily by mutations in JAK2, CALR, and myeloproliferative leukemia, leading to constitutive activation of the JAK-STAT pathway. Emerging evidence highlights mitochondrial dysfunction as a key factor in MPN pathogenesis, contributing to increased reactive oxygen species production, mitochondrial DNA mutations, and dysregulated mitochondrial dynamics, which collectively promote clonal expansion and apoptosis resistance. Targeting mitochondrial pathways has gained attention as a therapeutic strategy, with approaches including mitochondria-targeted antioxidants, metabolic inhibitors, and modulation of mitophagy and mitochondrial fission/fusion dynamics. However, challenges such as drug delivery specificity, therapeutic resistance, and off-target effects remain significant. Recent advances in precision medicine, incorporating genomic, transcriptomic, and proteomic profiling, offer a more personalized approach to MPN treatment by tailoring interventions to individual mutation patterns. Additionally, novel therapeutic strategies, including gene editing technologies, RNA-based therapies, and nanoparticle-mediated drug delivery systems, hold promise for overcoming current treatment limitations. The integration of artificial intelligence in drug discovery and biomarker identification further enhances the potential for targeted therapies. Future research should focus on refining these strategies, developing reliable biomarkers for patient stratification, and exploring combination therapies that enhance treatment efficacy while minimizing adverse effects. By addressing mitochondrial dysfunction as an underlying driver of MPNs, these emerging approaches have the potential to improve disease management, extend patient survival, and enhance quality of life. Also, this new approach of precision medicine allows patient stratification and ensures that treatments are formed according to the individual disease biology of each patient, which results in overall better outcomes.

Keywords:  combination drug therapy; drug delivery systems; mitochondrial DNA; mitochondrial dysfunction; myeloproliferative disorders; signal transduction

DOI:  https://doi.org/10.1097/MS9.0000000000003365
Ageing Res Rev. 2025 Sep 03. pii: S1568-1637(25)00238-7. [Epub ahead of print] 102892

Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging.

Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Helio José Coelho-Junior, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.

  Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial-nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.

Keywords:  DNA repair; biological aging; genomic instability; hallmarks of aging; mitochondrial dysfunction; telomeres

DOI:  https://doi.org/10.1016/j.arr.2025.102892
Stem Cells. 2025 Sep 04. pii: sxaf059. [Epub ahead of print]

The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.

Lars Thielecke, Kalpana Nattamai, Aishlin Hassan, Ingmar Glauche, Hartmut Geiger, Kerstin Cornils.

  The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.

Keywords:  aging; cellular barcodes; clonality; hematopoiesis; stem cell transplantation

DOI:  https://doi.org/10.1093/stmcls/sxaf059
Front Immunol. 2025 ;16 1626888

Iron overload promotes myeloid differentiation of normal hematopoietic stem cells and educates macrophage mediated immunosuppression in acute myeloid leukemia.

Feifei Yang, Shulin Luo, Dan Yang, Xiaoxi Cui, Dongyue Zhang, Hao Wang, Yifei Li, Wanzhen Xie, Lina Wang, Xiuqun Zhang, Guoguang Zheng, Xuezhong Zhang.

   Background: The hematopoietic ecosystem comprises both cellular components such as hematopoietic stem cells (HSCs) and immune cells as well as non-cellular components including iron. Systemic iron overload, which leads to serious complications and affects both patients' quality of life and overall survival, is a common clinical challenge in patients with acute myeloid leukemia (AML). We previously elucidated the direct effects of iron overload on AML cells. It's worth noting that iron overload remodels the hematopoietic ecosystem. However, whether and how remodeled leukemic microenvironment with overloaded iron regulates normal HSCs and immune cells, especially leukemia-associated macrophages (LAMs), in AML have not been elucidated.
Methods: The MLL-AF9-induced AML (MA9) cells were originated from c-kit+ BM cells enriched from C57BL/6J mice that infected with MSCV-MLL-AF9-GFP retrovirus. The MA9 AML mouse model was established by transplantation of MA9 cells into C57BL/6 mice. MA9 mice were i.p. administered with iron dextran every other day for a total of 6 times to established the iron overload MLL-AF9-induced AML mouse model (MA9/FE). HSC maintenance and differentiation was assessed by flow cytometry, cell proliferation, cell apoptosis, colony forming and competitive transplantation assays. LAM activation and function was analyzed by RNA-sequencing, flow cytometry and coculture assay. Intravenous clodronate liposome administration was employed to reduce LAMs in AML.
Results: Iron overload skewed myeloid differentiation of normal HSCs. Furthermore, iron overload affected LAMs in the AML microenvironment by promoting LAM polarization toward an M2 phenotype. Functionally, iron overload decreased the phagocytic function of LAMs against leukemia cells and inhibited LAM-induced T cell activation by acquiring a tolerogenic phenotype with aberrant immune checkpoints. Moreover, depletion of LAMs attenuated iron overload caused acceleration of AML progression.
Conclusions: Collectively, this study reveals the significance of iron overload in remodeling hematopoietic ecosystem and affecting HSC and LAM function in AML, providing new insights into the multifaceted role of iron overload in leukemia.

Keywords:  acute myeloid leukemia; immunosuppression; iron overload; leukemia-associated macrophages; myeloid differentiation

DOI:  https://doi.org/10.3389/fimmu.2025.1626888