bims-mithem 2026-02-01 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2026–02–01
ten papers selected by
Tim van Tienhoven, Erasmus Medical Center

Age-dependent role of histone deacetylase Sirt7 on haematopoiesis.
A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.
Repeated proliferative events ameliorate age-associated accumulation of DNA damage in HSPCs.
Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny.
Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.
Mitochondria in T‑cell tumor immunity and tumor therapies targeting mitochondria (Review).
Mitochondrial Dysfunction in Acute Kidney Injury: Intersections Between Chemotherapy and Novel Cancer Immunotherapies.
Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.

Stem Cells. 2026 Jan 29. pii: sxag005. [Epub ahead of print]

Age-dependent role of histone deacetylase Sirt7 on haematopoiesis.

Hannah Willems, Reinhard Bauer, Jörg P Müller.

  Sirt7 is a member of the sirtuin family of proteins, which are NAD+-dependent deacetylases and ADP-ribosyltransferases. It is involved in a wide range of cellular processes. To study the specific role of Sirt7 in haematopoiesis during aging, the gene was specifically inactivated in hematopoietic stem cells (HSC). Vav1 promoter mediated expression of CRE recombinase in floxed Sirt7 mice resulted in specific inactivation of Sirt7 in the haematopoietic stem and progenitor cells. Young mice exhibited a normal peripheral blood count and no detectable haematological aberrancies. Peripheral blood of 19-month-old Sirt7 knockout mice revealed a diminished abundance of lymphocytes, but elevated count of monocytes compared to control mice. The number of erythrocytes, platelets and haemoglobin concentration remained unchanged. In the bone marrow of aged mice, a reduced abundance of myeloid undifferentiated cells could be observed. The development of hepatomegaly due to Sirt7 gene inactivation could indicate a myeloproliferative influence. Taken together, our data demonstrate that Sirt7 functions as a critical suppressor on haematopoietic stem cells differentiation in aged mice.

Keywords:  Sirtuin7; Vav1-CRE; blood cell differentiation; haematopoietic stem cells; haematopoietic system; loxP

DOI:  https://doi.org/10.1093/stmcls/sxag005
Aging Cell. 2026 Feb;25(2): e70394

A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.

Ryan R White, Kun Xiong, Matthew Wakai, Allison Surian, Christina Adler, Nicole Negron, Min Ni, Tea Shavlakadze, Yu Bai, David J Glass.

Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.

DOI: https://doi.org/10.1111/acel.70394
Front Immunol. 2025 ;16 1740433

Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.

Vasantharaja Raguraman, Yogamaya Divakar Prabhu, Gopal Viswanathan Velmurugan, Gerhard C Hildebrandt, Senthilnathan Palaniyandi.

  Mitochondrial fusion and fission regulate mitochondrial morphology and homeostasis, both of which are essential for maintaining cellular health. Free mitochondria and mitochondrial-containing extracellular vesicles have emerged as key mediators of pathological processes. Conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) damage and lead to impaired mitochondrial function, including biogenesis and respiration, as well as elevated reactive oxygen species (ROS), which contribute to the development of inflammatory conditions as well as activation of antigen presenting cells, the latter being key players in acute graft versus host pathophysiology (GVHD). This leads to increased T-cell activation and proliferation, which increases alloreactivity and drives GVHD. Dysregulated mitochondrial dynamics lead to the release of mitochondrial DNA and formylated peptides, which act as Damage-Associated Molecular Patterns (DAMPs) and trigger cellular homeostatic imbalances, ultimately leading to more inflammation. The understanding that mitochondrial dysfunction contributes to GVHD offers novel therapeutic strategies, including blocking DAMP signaling and modulating immune cell metabolism to restore mitochondrial health. This review aims to understand mitochondrial homeostasis in both recipient and donor cells. This is crucial for understanding GVHD pathophysiology and developing mitochondria-targeted therapies or mitochondrial transfer strategies as potential therapeutic interventions for GVHD.

Keywords:  DAMP (Damage Associated Molecular Pattern); Graft versus host disease (GVHD); hematopoietic cell transplantation (HCT); mitochondria transfer; mitochondrial DNA

DOI:  https://doi.org/10.3389/fimmu.2025.1740433
Life Sci Alliance. 2026 Apr;pii: e202503337. [Epub ahead of print]9(4):

Repeated proliferative events ameliorate age-associated accumulation of DNA damage in HSPCs.

Shubham Haribhau Mehatre, Harsh Agrawal, Irene Mariam Roy, Sarah Schouteden, Satish Khurana.

Upon aging, hematopoietic stem cells show accumulation of DNA damage that has been causally linked with their functional decline, with debatable role of proliferative events. In this study, we sought to enquire the effect of increased proliferation rate in hematopoietic stem and progenitor cells (HSPCs) on hematopoietic aging. Multiple rounds of blood withdrawals were performed during adult life to maintain a higher proliferation rate in HSPC population in mice. Our experiments showed little effect of increased proliferation on age-associated functional decline in the hematopoietic system. However, we noted a decrease in the double-strand breaks accumulated with age after the serial bleeding regimen. Analysis of scRNA-Seq data from mouse and human HSPCs showed enrichment of DNA damage response pathways. Importantly, we demonstrate that the induction of HSPC proliferation in aged mice was sufficient to activate the DNA damage response in vivo and decrease the load of double-strand breaks. Hence, these results show that repeated blood withdrawals equivalent to clinical blood donation clear DNA damages without impacting the functioning of HSPCs.

DOI: https://doi.org/10.26508/lsa.202503337
Haematologica. 2026 Jan 29.

Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny.

Tal Bachrach, Adrian Duek, Liran I Shlush.

Clonal hematopoiesis (CH) is driven by the age-associated expansion of hematopoietic stem and progenitor cells (HSPCs) that harbor somatic driver mutations; however, the mechanisms underlying their long-term persistence remain incompletely understood. This review frames CH through the lens of inclusive fitness, proposing that mutant pre-leukemic HSPCs enhance their evolutionary success not only through intrinsic self-renewal advantages, but also via indirect effects mediated by their differentiated progeny. We synthesize evidence showing that mutant immune cells promote inflammatory microenvironments that selectively impair wild-type HSCs while reinforcing mutant self-renewal, establishing self-sustaining feedback loops that shape clonal dynamics and systemic disease risk.

DOI: https://doi.org/10.3324/haematol.2025.287480
Curr Issues Mol Biol. 2025 Dec 14. pii: 1042. [Epub ahead of print]47(12):

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.

Mi Eun Kim, Yeeun Lim, Jun Sik Lee.

  Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2-KEAP1 antioxidant system, the cGAS-STING innate immune pathway, and the PINK1-Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD+ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases.

Keywords:  chronic inflammation; immuno-metabolism; metabolic reprogramming; mitochondrial dysfunction; therapeutic targeting

DOI:  https://doi.org/10.3390/cimb47121042
Oncol Rep. 2026 Apr;pii: 59. [Epub ahead of print]55(4):

Mitochondria in T‑cell tumor immunity and tumor therapies targeting mitochondria (Review).

Minjie Zhou, Yijie Xie, Zhipeng Liu, Yi He, Yibing Yin, Keyu Chen, Zhengyu Zhao, Chengshun Zhang, Dingjun Cai.

  Mitochondria are central to cellular metabolic reprogramming, and their energy metabolism pathways are indispensable for T‑cell activation, proliferation and differentiation. Mitochondrial metabolic reprogramming enhances T‑cell activity and antitumor function. Mitochondrial dynamics, including fusion, fission and transfer, regulate T‑cell tumor immune function by modulating the number, morphology and distribution of mitochondria, which is vital for the antitumor effects of T cells. The release of mitochondrial DNA can activate multiple innate immune signaling pathways, such as cyclic GMP‑AMP synthase‑stimulator of interferon genes, Toll‑like receptor 9, and NOD‑, LRR‑, and pyrin domain‑containing protein 3, serving a complex regulatory role in shaping the tumor immunosuppressive microenvironment and T‑cell antitumor immune responses. Notably, mitochondrial dysfunction is a major driver of tumor initiation and progression. T‑cell mitochondrial metabolic reprogramming, dynamic changes and mitochondrial DNA release all affect the antitumor immunity of tumor‑infiltrating T cells. The present review focuses on the relationship between mitochondria and T‑cell antitumor immune responses, exploring the core role of mitochondria in T‑cell tumor immunity from multiple aspects, including mitochondrial energy metabolism, mitochondrial dynamics and mitochondrial DNA. In addition, the present review examines state‑of‑the‑art research on antitumor therapies targeting mitochondria from multiple perspectives, with the aim of providing a reference for developing mitochondria‑targeted antitumor immunotherapy strategies.

Keywords:  T cell; mitochondria; mitochondrial DNA; mitochondrial dynamics; mitochondrial metabolism; tumor immunity

DOI:  https://doi.org/10.3892/or.2026.9064
Biomolecules. 2026 Jan 12. pii: 120. [Epub ahead of print]16(1):

Mitochondrial Dysfunction in Acute Kidney Injury: Intersections Between Chemotherapy and Novel Cancer Immunotherapies.

Zaroon Zaroon, Carlotta D'Ambrosio, Filomena de Nigris.

  Acute kidney injury (AKI) remains a major clinical challenge, with high morbidity and limited therapeutic options. In recent years, mitochondria have gained considerable attention as key regulators of the metabolic and immune responses during renal injury. Beyond their classical role in ATP production, mitochondria participate directly in inflammatory signaling, releasing mitochondrial DNA and other DAMPs that activate pathways such as TLR9, cGAS-STING, and the NLRP3 inflammasome. At the same time, immune cells recruited to the kidney undergo significant metabolic shifts that influence whether injury progresses or resolves. Increasing evidence also shows that immune-modulating therapies, including immune checkpoint inhibitors and innovative cell-based immunotherapies, can influence mitochondrial integrity, thereby altering renal susceptibility to injury. This review first summarizes the established knowledge on mitochondrial dysfunction in AKI, with emphasis on distinct mechanistic pathways activated by chemotherapy and immunotherapy. It then discusses emerging mitochondrial-targeted therapeutic strategies, logically integrating preclinical insights with data from ongoing and proposed clinical trials to present a coherent translational outlook.

Keywords:  acute kidney injury (AKI); immune checkpoint inhibitor; inflammasome; mitochondrial dysfunction; nephrotoxicity

DOI:  https://doi.org/10.3390/biom16010120
Mol Cancer. 2026 Jan 27.

Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.

Hongling Zhong, Renjie Pan, Yuzhen Ouyang, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Hucheng Li, Tianfang Peng, Pan Chen.

  Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.

Keywords:  Cancer Metabolism Reprograming; Mitochondrial DNA (mtDNA) Damage; Mitochondrial Homeostasis; Mitochondrial-Targeted Therapies; Tumor Microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02571-3
Blood. 2026 Jan 29. pii: blood.2025030055. [Epub ahead of print]

Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.

Steven Ngo, Giuseppe Alessandro D'Agostino, Despoina Papazoglou, Fatihah Mohamad Nor, Katja Finsterbusch, Khadidja Habel, Alessandra Ferrelli, Fernando Anjos-Afonso, Dominique Bonnet.

The Bcl2 inhibitor venetoclax in combination with the hypomethylating agents azacitidine (ven/aza) has become increasingly utilized clinically for the treatment of many hematological malignancies. Whilst its effects on malignant cells have been extensively studied, its impact to the surrounding bone marrow microenvironment (BME) remains unexplored. In this study, we report that ven/aza therapy causes significant damage to the BME of mice. Comparatively high Bcl2 expression in the sinusoidal endothelial cell compartment (SEC) amongst all stromal subtypes, results in high sensitivity to ven/aza treatment, causing selective depletion of SECs and breakdown in cell-cell communication pathways in the endothelial cell (EC) network, leading to vascular leakiness in the BM. Furthermore, our detailed transcriptomic and imaging studies reveals significant downregulation of essential adhesion molecules in residual SECs, leading to significant defects in human hematopoietic stem/progenitor cell (HSPC) homing and engraftment of hematopoietic stem cells (HSCs) after ven/aza treatment. To conclude, our study showcases that maintaining SEC integrity in response to ven/aza therapy may play a key factor in achieving effective engraftment of donor derived HSCs.

DOI: https://doi.org/10.1182/blood.2025030055