bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–09–06
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Horizontal mitochondrial transfer: an emerging field in cell biology.
  2. Loss of CALU disrupts intracellular Ca2+ homeostasis and triggers apoptosis in glioma cells.
  3. Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.
  4. Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
  5. A consensus roadmap from the SENESCENCE2030 network towards precision senescence medicine.
  6. Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
  7. Targeting cellular senescence mitigates chemotherapy-induced bone loss in young and aged mice.
  8. Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration.
  9. GLP-1 receptor agonism extends median lifespan in mice.
  1. Trends Cell Biol. 2026 Sep 04. pii: S0962-8924(26)00168-6. [Epub ahead of print]
    Horizontal mitochondrial transfer: an emerging field in cell biology.
    Michael V Berridge, Zuzana Nahacka, Katerina Komrskova, Minghao Zheng, Jiri Neuzil.
      The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.012
  2. Cell Calcium. 2026 Aug 16. pii: S0143-4160(26)00075-8. [Epub ahead of print]137 103182
    Loss of CALU disrupts intracellular Ca2+ homeostasis and triggers apoptosis in glioma cells.
    Lingyun Wu, Tong Wu, Hao Liu, Ruzhen Dai, Yan Zhou, Yifan Xu, Bin Huang.
      Glioma is an aggressive primary tumor of the central nervous system. Calcium (Ca2+) signaling between the ER and mitochondria is essential for cell survival and death regulation. Calumenin (CALU), an ER-resident Ca2+-binding protein, has been implicated in several cancers, but its role in glioma remains unclear. Public datasets (TCGA, CGGA) were analyzed to assess CALU expression and prognosis. We manipulated CALU through transfection technology and tested its role in Ca2+ responses, intracellular Ca2+ store-associated fluorescence, and mitochondrial Ca2+-associated fluorescence signals by means of Fluo-4, Mag-Fluo-4, and Rhod-2 probes, respectively. Mitochondrial Ca2+uptake was further assessed using an isolated mitochondrial Calcium Green-5 N assay. Mitochondrial function was assessed through the detection of MMP and mPTP utilizing JC-1 staining and calcein-AM/cobalt assay. Mitochondrial ROS and total ROS were estimated via mitoSox red staining and DCFH-DA assay. The cell apoptosis was appraised utilizing flow cytometry and TUNEL staining. A xenograft model using U87 glioma cells was established to further explore the role of CALU in vivo. CALU expression was highly expressed in gliomas and correlated with poor survival and mitochondrial Ca2+ transport genes. CALU depletion reduced intracellular Ca2+ store-associated fluorescence, enhanced store-operated Ca2+ entry (SOCE), and induced sustained cytosolic Ca2+elevation accompanied by enhanced mitochondrial Ca2+-associated fluorescence signals and enhanced mitochondrial Ca2+ uptake. These changes were associated with decreased MMP, increased mitochondrial calcein fluorescence, elevated ROS generation, and facilitated apoptosis. In vivo, CALU knockdown reduced tumor growth, increased 4-HNE and cleaved caspase-3 expression and reduced Ki-67 expression, which were partially reversed by NAC treatment. These findings suggest that CALU may contribute to the maintenance of intracellular Ca2+ homeostasis in glioma cells. Loss of CALU induces SOCE-associated Ca2+dysregulation, mitochondrial dysfunction, and ROS-mediated apoptosis, highlighting CALU as a potential therapeutic target for glioma.
    Keywords:  Apoptosis; CALU; Calcium; Endoplasmic reticulum; Glioma; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2026.103182
  3. Nat Neurosci. 2026 Sep 02.
    Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.
    Jun Gao, Haixin Zhao, Xiao Han, Lingmin Zeng, Jingqi Pan, Guangqin Liu, Xuechen Wei, Changwei Liu, Wenjun Wu, Siqi Chen, Jiayi Chen, Ting Li, Jiye Yin, Tao Zhou, Xue-Min Zhang, Ai-Ling Li, Teng Li, Xin Pan.
      Addictive substances hijack the brain's reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a therapeutic target for addiction treatment.
    DOI:  https://doi.org/10.1038/s41593-026-02421-x
  4. Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00343-9. [Epub ahead of print]232 108428
    Crosstalk between UPR and mitochondria: The triad of ER-mitochondria contacts, Ca²⁺, and ROS.
    Ester Zito, György Hajnóczky.
      Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.
    Keywords:  CHOP; Ca²⁺ handling; ER stress; ERO1; ER–mitochondria contact sites (ERMCs); IP₃ receptor (IP₃R); Mitochondrial permeability transition pore (mPTP); Pharmacological therapy; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.phrs.2026.108428
  5. Nat Aging. 2026 Sep 03.
    A consensus roadmap from the SENESCENCE2030 network towards precision senescence medicine.
    Aniello Cerrato, Antonella Farsetti, Laura Bordoni, Raquel Rua Martins, Iker Bengoetxea de Tena, Ivana Vrhovac Madunic, Marziyya Mammadova, Stefano Raviola, Mohamad Rima, Minenur Ozturk, Rosa Spinelli, Nicoleta Moisoi, Francesco Nicoli, Luca Pangrazzi, An Wouters, Ashraf Albrakati, Mahmoud Abdellatif, Lorna W Harries, Giuseppe Martini, Yannis Missirlis, Brunella Mongiardi, Sonia de Pascual-Teresa, Daniel Moreno-Blas, Ayse Cakir Gungor, Diana Cunha-Reis, Cleo L Bishop, Johannes Grillari, Pasquale Maffia, Marco Demaria.
      
    DOI:  https://doi.org/10.1038/s43587-026-01222-y
  6. Nat Commun. 2026 Sep 04. pii: 9151. [Epub ahead of print]17(1):
    Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
    Diego Gilioli, Simona Fusco, Teresa Tavella, Tatiana Volpari, Antonella Santoro, Martin Schönlein, Kety Giannetti, Edoardo Carsana, Nicolò Gualandi, Roberta Noberini, Chiara Brombin, Salvatore Russo, Sara Feola, Yvonne Giannoula, Rui M M Branca, Janne Lehtiö, Tiina M Sikanen, Markus Haapala, Laura Passerini, Angela Andrisani, Giacomo Farina, Alessia Zangari, Anastasia Conti, Lucrezia Della Volpe, Matteo Barcella, Stefano Beretta, Federico Mario Aletti, Matteo Giovanni Carrabba, Silvia Gregori, Chiara Bonini, Ivan Merelli, Fabio Ciceri, Vincenzo Cerullo, Tiziana Bonaldi, Luca Vago, Clemens A Schmitt, Raffaella Di Micco.
      Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.
    DOI:  https://doi.org/10.1038/s41467-026-76853-1
  7. Geroscience. 2026 Sep 02.
    Targeting cellular senescence mitigates chemotherapy-induced bone loss in young and aged mice.
    David J Izquierdo, Enrique Blancarte-Hernandez, Charles A Schurman, Birgit Schilling, Anna Woloszyk, Leonardo Aguilar, Adam Salmon, Vaida Glatt.
      Chemotherapy-induced bone loss represents a major clinical challenge, particularly in aging populations, yet the contribution of cellular senescence to this process and its therapeutic potential remain incompletely understood. Here, we investigated the role of chemotherapy-induced cellular senescence in mediating skeletal deterioration following chemotherapy and evaluated the therapeutic potential of senolytic treatment. Young (3-month-old) and aged (20-month-old) male and female mice were treated with doxorubicin (DX), a chemotherapeutic agent, dasatinib/quercetin (DQ), senolytic agents, or their combination (DX/DQ). Chemotherapy-induced hallmark features of accelerated skeletal aging, including trabecular bone loss, increased marrow adiposity, and upregulation of senescence-associated and inflammatory gene expression. These effects were sex- and age-dependent and were more pronounced in females. Senolytic treatment with DQ partially restored osteogenic gene expression, including Alpl, Runx2, and Dmp1, and reduced marrow adiposity, particularly in aged females, indicating preservation of bone marrow niche function. Proteomic analysis of cortical bone revealed that DX-induced cellular senescence was associated with extracellular matrix remodeling and a metabolic shift toward glycolysis, characterized by increased inflammatory collagen isoforms and glycolytic enzymes. DQ treatment partially reversed these molecular signatures, including restoration of several extracellular matrix proteins associated with bone architecture and mineralization. Despite these molecular improvements, recovery of trabecular bone architecture remained modest, suggesting that senolytic-mediated molecular remodeling precedes detectable skeletal recovery. Collectively, these findings support a model in which chemotherapy-induced bone loss is driven by both early osteoblast suppression and senescence-driven microenvironmental dysfunction, identifying cellular senescence as a potential therapeutic target for preserving skeletal health following chemotherapy.
    Keywords:  Bone aging; Bone marrow microenvironment; Cellular senescence; Chemotherapy-induced bone loss; Dasatinib and quercetin; Doxorubicin; Mouse model; Osteoporosis; Senolytics
    DOI:  https://doi.org/10.1007/s11357-026-02485-4
  8. Mol Biomed. 2026 Sep 01. pii: 155. [Epub ahead of print]7(1):
    Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration.
    Haoran Hu, Tao Han, Qiyuan Huang, Ping Gong, Jiangxi Liu, Hao Wang, Xiaowei Ling, Kang Wang, Shuangshuang Liu, Yue Yu, Ting Luo, Feng Cheng, Xiaoxiao Liu.
      The liver possesses an extraordinary capacity to regenerate after injury or surgical resection, a process highly dependent on the coordinated orchestration of the immune microenvironment. Although macrophages are recognized as pivotal coordinators of hepatic tissue repair, the precise checkpoints governing their functional transitions during regeneration remain elusive. Here, we identify the glutamine transporter SLC1A5 (Solute Carrier Family 1 Member 5) as a critical metabolic gatekeeper of macrophage function during liver regeneration. Using a mouse model of partial hepatectomy, we show that SLC1A5 is markedly upregulated in monocyte-derived macrophages at the peak of regeneration. Myeloid specific deletion of Slc1a5 (Slc1a5fl/flLyz2cre) severely impairs hepatocyte proliferation and diminishes the expression of macrophage derived regenerative factors. Mechanistically, Slc1a5 deficiency depletes intracellular glutamine, which triggers macrophage senescence and drives a pro-inflammatory phenotype. This senescent state selectively downregulates Gas6 (Growth Arrest Specific 6), a crucial bridging ligand for efferocytosis, thereby impairing apoptotic cell clearance and exacerbating local inflammation. Strikingly, exogenous Gas6, senolytic Quercetin therapy, or in vivo L-glutamine supplementation successfully alleviates macrophage senescence, reinstates Gas6 mediated efferocytosis, and rescues defective liver regeneration. Collectively, our findings reveal a novel 'Slc1a5-glutamine-senescence-efferocytosis' axis that dictates macrophage driven tissue repair. This study not only uncovers a fundamental immunometabolic mechanism but also highlights glutamine supplementation and senolytics therapy as promising clinically strategies to accelerate liver regeneration.
    Keywords:  Cell senescence; Efferocytosis; Liver regeneration; Macrophage; SLC1A5
    DOI:  https://doi.org/10.1186/s43556-026-00526-0
  9. Nat Aging. 2026 Sep 03.
    GLP-1 receptor agonism extends median lifespan in mice.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-026-01224-w
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