bims-mithem Biomed News
on Mitochondria in Hematopoiesis
Issue of 2026–04–12
seven papers selected by
Tim van Tienhoven, Erasmus Medical Center
  1. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  2. Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
  3. Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
  4. Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
  5. Mitochondrial dynamics and cancer: mechanisms and targeted therapy.
  6. Innovative strategies for immune thrombocytopenia treatment: immunomodulatory mechanisms and clinical potential of mesenchymal stem cells.
  7. Chemotherapy-induced reactive myelopoiesis promotes expansion of immunosuppressive neutrophil-like monocytes in mice and humans.
  1. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  2. Redox Biol. 2025 Dec 20. pii: S2213-2317(25)00489-6. [Epub ahead of print]93 103976
    Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
    Kai-Yang Chen, Hoi-Chun Chan, Wan-Wan Lin, Chi-Ming Chan.
      Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly and has a multifactorial etiology involving advanced age, genetic susceptibility, and environmental risk factors. Accumulating evidence suggests that mitochondrial dysfunction is a central pathogenic mechanism in AMD, particularly in the retinal pigment epithelium (RPE). The RPE is critical for retinal homeostasis, and its high metabolic activity renders it vulnerable to age-related mitochondrial dysfunction. In AMD, the core processes of mitochondrial dynamics-fission, fusion, biogenesis, and mitophagy-are profoundly dysregulated, leading to a fragmented and dysfunctional mitochondrial network. This failure of quality control results in bioenergetic deficits, excessive oxidative stress, and the release of damage-associated molecular patterns that fuel chronic inflammation and complement-mediated damage. Experimental models and human tissue studies have strengthened the link between mitochondrial dysfunction and AMD pathology, revealing structural abnormalities, mitochondrial DNA (mtDNA) damage, and altered metabolic signatures. Therapeutic strategies targeting mitochondrial pathways, including mitochondria-targeted antioxidants, dynamic modulators, and enhancers of biogenesis and mitophagy, such as agents that restore defective mitophagosome formation, represent promising avenues for intervention. As the field advances, the integration of biomarker development and personalized approaches holds the potential to transform the clinical landscape of AMD by addressing the root causes of cellular dysfunction.
    Keywords:  Age-related macular degeneration; Biogenesis; Fission; Fusion; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.redox.2025.103976
  3. Circ Res. 2026 Apr 10. 138(8): e326985
    Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
    Xi Fang, Åsa B Gustafsson.
      Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.
    Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
  4. bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]
    Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
    Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.
      Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.
    DOI:  https://doi.org/10.64898/2026.03.29.715103
  5. Cell Biol Toxicol. 2026 Apr 06.
    Mitochondrial dynamics and cancer: mechanisms and targeted therapy.
    Aixin Wang, Xinyu Ye, Yumeng Zhao, Chao Zhang.
      Mitochondria, as key organelles in eukaryotic cells, regulate cellular energy homeostasis and functional integrity through dynamic processes, including fission, fusion, autophagy, and transport, underpinned by precise molecular mechanisms. In healthy cells, the equilibrium of mitochondrial dynamics ensures network quality control and metabolic coordination. In contrast, cancer cells exhibit multi-dimensional dysregulation characterized by hyperactive fission, impaired fusion, and compensatory upregulation of respiratory chain assembly factors, creating a state of "morphology-function decoupling". These alterations drive tumor progression by reprogramming cellular metabolism, promoting proliferation, inhibiting apoptosis, enhancing migration and drug resistance, and facilitating immune evasion. This review elucidates the molecular mechanisms underlying mitochondrial dynamics, their dysregulation in cancer, and their influence on tumor behavior, while also addressing the core challenges of current targeted therapeutic strategies and the novel therapeutic paradigm of "network remodeling", offering new insights into tumor biology and precision cancer therapy.
    Keywords:  Cancer; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Targeted therapy
    DOI:  https://doi.org/10.1007/s10565-026-10174-3
  6. Stem Cell Res Ther. 2026 Apr 07.
    Innovative strategies for immune thrombocytopenia treatment: immunomodulatory mechanisms and clinical potential of mesenchymal stem cells.
    Xin Zhou, Ningning Shan.
      Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by increased platelet destruction and impaired megakaryopoiesis within a dysregulated bone marrow niche. Conventional therapies often achieve only transient platelet recovery, failing to restore immune tolerance, thereby underscoring the need for mechanism-based therapeutic strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates due to their ability to modulate immune responses and repair the hematopoietic microenvironment. This review synthesizes current evidence regarding the biological properties, immunomodulatory mechanisms, and therapeutic applications of MSCs in ITP, emphasizing intrinsic abnormalities of patient-derived MSCs and the corrective potential of exogenous MSCs from distinct tissue sources. It further integrates emerging insights into MSC functional heterogeneity, optimization of culture conditions, priming strategies, and cellular engineering approaches that may enhance therapeutic efficacy and safety. By highlighting the interplay between immune tolerance restoration and bone marrow niche remodeling, this review provides a translational framework that links mechanistic understanding to the future clinical development of MSC-based therapies for ITP.
    Keywords:  Bone marrow niche; Immune thrombocytopenia; Immunomodulation; Mesenchymal stem cells
    DOI:  https://doi.org/10.1186/s13287-026-05000-w
  7. JCI Insight. 2026 Mar 31. pii: e198360. [Epub ahead of print]
    Chemotherapy-induced reactive myelopoiesis promotes expansion of immunosuppressive neutrophil-like monocytes in mice and humans.
    Huidong Shi, Zhi-Chun Ding, Ogacheko D Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C Hedrick, Locke J Bryan, Gang Zhou.
      Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4⁺CX3CR1⁻ monocyte subset, exhibited potent T-cell suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo-like cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.
    Keywords:  Immunology; Monocytes; Neutrophils; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.198360
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