bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–07–19
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. IRF1 Inhibits Therapy-Induced Senescence of Glioblastoma Cells Through OAS2.
  2. Why do astronauts' bodies waste away? Space-station study points to mitochondria.
  3. A high-fat, low-carbohydrate diet can feed intestinal tumours.
  4. Lysosomes and lysosomal dysfunction in ageing biology.
  5. The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.
  6. Oncogene inactivation-induced senescence facilitates tumor relapse.
  7. Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
  8. Reply to Zhou et al.: Exercise, caloric restriction, and immunotherapy responsiveness in 4T1 breast cancer progression.
  9. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  10. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  1. Cells. 2026 Jun 24. pii: 1149. [Epub ahead of print]15(13):
    IRF1 Inhibits Therapy-Induced Senescence of Glioblastoma Cells Through OAS2.
    Genli Ma, Weiwei Huang, Hangcong Yan, Bin Shen, Shanli Zhu, Xingxing Xu.
      Glioblastoma (GBM), a highly aggressive brain tumor, is characterized by poor treatment outcomes and a strong tendency to recur after therapy. Therapy-induced senescence (TIS) of GBM cells has emerged as a key driver of GBM progression and relapse. Temozolomide (TMZ), which serves as the standard chemotherapeutic agent for GBM, is known to induce senescence; however, the molecular mechanisms underlying this process remain largely unknown. In this work, we found that interferon regulatory factor-1 (IRF1) was downregulated in TMZ-induced senescent GBM cells. Functionally, knockdown of IRF1 increased the activity of senescence-associated β-galactosidase (SA-β-gal), reduced protein expression of Lamin B1, inhibited cell division, and enhanced senescence-associated secretory phenotype (SASP) of GBM cells, indicating that downregulation of IRF1 promotes senescence of GBM cells. Conversely, overexpression of IRF1 partially reversed TMZ-induced senescence. Further exploration revealed that downregulation of IRF1 reduced the expression of 2',5'-oligoadenylate synthetase 2 (OAS2), and overexpression of IRF1 increased the expression of OAS2. OAS2 was also downregulated in TMZ-induced senescent GBM cells, and knockdown of OAS2 induced senescence of GBM cells as well. Taken together, our study reveals that IRF1 inhibits TMZ-induced senescence of GBM cells through OAS2, highlighting a novel regulatory axis that may offer potential therapeutic targets for improving GBM treatment.
    Keywords:  IRF1; OAS2; glioblastoma; senescence
    DOI:  https://doi.org/10.3390/cells15131149
  2. Nature. 2026 Jul 16.
    Why do astronauts' bodies waste away? Space-station study points to mitochondria.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-02089-0
  3. Nature. 2026 Jul 15.
    A high-fat, low-carbohydrate diet can feed intestinal tumours.
    Souvik Patra, Evan C Lien.
      
    Keywords:  Cancer; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02039-w
  4. Nat Cell Biol. 2026 Jul 15.
    Lysosomes and lysosomal dysfunction in ageing biology.
    Matthew L Steinhauser, Yuan Liu, Stacey J Sukoff Rizzo, Bill B Chen, Toren Finkel, Jay Xiaojun Tan.
      Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-02007-6
  5. Nat Commun. 2026 Jul 15.
    The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.
    Dejun Xu, Shuaifei Song, Qingmiao Shi, Zhiling Zhao, Wenhao Zhao, Lei Wang, Guangxin E, Yanguo Han, Yongju Zhao, Zhongquan Zhao.
      Mitochondrial dysfunction and epigenetic alterations play critical roles in aging-related diseases, yet the molecular mechanisms linking mito-nuclear crosstalk to ovarian aging remain poorly understood. Here, single-cell transcriptome analysis of aging ovaries revealed senescence-associated hallmark alterations, including abnormally elevated mitochondrial metabolism, disrupted histone modification patterns, and enrichment of the senescence-associated secretory phenotype (SASP). We demonstrated that impaired SIRT5-mediated desuccinylation constitutes a key driver of ovarian aging. Mechanistically, we identified succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) in the tricarboxylic acid (TCA) cycle as the main target of SIRT5-mediated desuccinylation. SUCLG2 desuccinylation at lysine residues K93 and K101 enhanced its protein stability and activity, thereby improving mitochondrial function upon cellular senescence. However, SUCLG2 hypersuccinylation specifically increased H4K8ac through acetyl-CoA accumulation in nucleus, leading to the overexpression of metabolism-related genes to compensate for the energy demand deficiency caused by decreased mitochondrial function during cellular senescence. In vivo functional studies demonstrated that acetyl-CoA oversupply accelerated ovarian aging, whereas ovarian gene therapy employing a SUCLG2 desuccinylation mutant ameliorated this condition. This study illuminates the molecular mechanisms underlying ovarian aging and identifies the SIRT5-SUCLG2 axis as a promising therapeutic target for age-related ovarian dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-75502-x
  6. Nat Commun. 2026 Jul 15. pii: 6244. [Epub ahead of print]17(1):
    Oncogene inactivation-induced senescence facilitates tumor relapse.
    Philipp Schmitt, Katrin Hönig, Maria Teresa Norcia, Marta F Nogueira, Viktoria Flore, Inés Simó Vesperinas, Maria Villoro-Agud, Lushan Peng, Zuhal Safyürek, Mehreen Tariq, Ana Milojkovic, Kathleen Anders, Evelin Schröck, Sascha Sauer, Bora Uyar, Altuna Akalin, Gerald Willimsky, Simon Haas, Inmaculada Martínez-Reyes, Thomas Blankenstein.
      Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers, but their long-term benefit is often limited by resistance and relapse. Here we show that oncogene inactivation rapidly induces senescence and a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposes tumors to relapse, accompanied by polyploidy, chromosomal instability, acquisition of alternative oncogenic pathways including mouse double minute 2 homolog (Mdm2) upregulation, and tumor microenvironmental remodeling toward neovascularization and immunosuppression. Spectral flow cytometry reveals a shift from an immune-activated to an immunosuppressive milieu during relapse. OIIS features are also observed in human BRAFV600E melanoma cells treated with vemurafenib, supporting clinical relevance. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-026-75021-9
  7. Science. 2026 Jul 16. 393(6808): eaea3075
    Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
    Yuting Jessy Tan, Travis E Conley, Fuwen Yao, Fernando J García-Marqués, Damilola E Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A Belk, Oliver Soehnlein, Sharon J Pitteri, Katrin I Andreasson.
      Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.
    DOI:  https://doi.org/10.1126/science.aea3075
  8. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2617811123
    Reply to Zhou et al.: Exercise, caloric restriction, and immunotherapy responsiveness in 4T1 breast cancer progression.
    Amanda Garrido, Nathan L Price, Michel Bernier, María Carmen Gómez-Cabrera, Rafael de Cabo.
      
    DOI:  https://doi.org/10.1073/pnas.2617811123
  9. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  10. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
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