bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–01–11
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Tmbim5 and Slc8b1 cooperate in tissue-specific mitochondrial calcium regulation in zebrafish.
  2. AKG-TET axis is central to senescence plasticity.
  3. p53 increases phospholipid headgroup scavenging in senescence.
  4. USP10 promotes glioma stem cell maintenance and glioblastoma growth by antagonizing DTX3L-mediated SATB2 ubiquitination.
  5. Mitochondrial control of fuel switching via carnitine biosynthesis.
  6. Crosstalk between TGF-β and Wnt/β-catenin signaling drives fibrogenic and stem-like phenotypes in senescent MDA-MB-231 breast cancer cells.
  7. Nutrient requirements of organ-specific metastasis in breast cancer.
  1. Commun Biol. 2026 Jan 08.
    Tmbim5 and Slc8b1 cooperate in tissue-specific mitochondrial calcium regulation in zebrafish.
    Iga Wasilewska, Łukasz Majewski, Dobrochna Adamek-Urbańska, Sofiia Baranykova, Paulina Castañeda-Tamez, Ilka Wittig, Matylda Macias, Aleksandra Szybińska, Axel Methner.
      Mitochondrial calcium homeostasis involves coordinated uptake via the mitochondrial calcium uniporter (MCU) and efflux through sodium-dependent NCLX (encoded by SLC8B1) and/or TMEM65. We investigated TMBIM5, a proposed bidirectional mitochondrial calcium/proton transporter, by generating zebrafish lacking tmbim5, slc8b1, plus tmbim5/mcu and tmbim5/slc8b1 double knockouts. Tmbim5-deficient fish exhibited growth impairment, muscle atrophy, and increased brain cell death. tmbim5/mcu double knockouts showed no additive effects, arguing against Tmbim5 functioning as an independent calcium uptake pathway. slc8b1 knockouts had no major phenotype but showed attenuated, although not abolished sodium-dependent mitochondrial calcium efflux. tmbim5/slc8b1 double knockouts showed altered mitochondrial calcium handling with reduced uptake and efflux. Remarkably, brain phenotypes were rescued while muscle dysfunction was exacerbated in double mutants, corresponding to restored mitochondrial membrane potential in brain tissue and decreased calcium levels in muscle. These findings suggest that TMBIM5 functions as an auxiliary calcium efflux pathway cooperating with NCLX in a tissue-specific manner.
    DOI:  https://doi.org/10.1038/s42003-025-09494-7
  2. iScience. 2026 Jan 16. 29(1): 114298
    AKG-TET axis is central to senescence plasticity.
    Shin Akakura, Siamak Tabibzadeh.
      Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating TET expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence. Conversely, augmenting AKG bioavailability or TET expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.
    Keywords:  Biochemistry; cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114298
  3. Nat Cell Biol. 2026 Jan 07.
    p53 increases phospholipid headgroup scavenging in senescence.
    Jossie J Yashinskie, Xianbing Zhu, Grace H McGregor, Karl A Wessendorf-Rodriguez, Katrina Paras, Julia S Brunner, Benjamin T Jackson, Abigail Xie, Richard Koche, Christian M Metallo, Lydia W S Finley.
      Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.
    DOI:  https://doi.org/10.1038/s41556-025-01853-0
  4. Nat Commun. 2026 Jan 08. 17(1): 164
    USP10 promotes glioma stem cell maintenance and glioblastoma growth by antagonizing DTX3L-mediated SATB2 ubiquitination.
    Mengyue Guo, Wenlong Luo, Peng Ling, Hong Lei, Lihua Li, Chao Duan, Zhen Xue, Min Zhang, Xiaoyan Zhang, Wendai Bao, Wenchao Zhou, Jianghong Man, Suojun Zhang, Kai Shu, Jun Qin, Xiuxing Wang, Zhiqiang Dong, Weiwei Tao.
      Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear matrix-associated protein with a pivotal role in glioblastoma (GBM) progression. However, the mechanisms underpinning aberrant SATB2 expression remain elusive. Here, we identify the ubiquitin specific peptidase 10 (USP10) as a deubiquitinase and the deltex E3 ubiquitin ligase 3 L (DTX3L) as a ubiquitin ligase of SATB2 in glioma stem cells (GSCs). USP10 and DTX3L regulate SATB2 ubiquitination at the K266 residue through mutually exclusive interactions and opposing activities. USP10, enriched in GSCs, is induced by transcription factor YY2. Knockdown of USP10 or overexpression of DTX3L markedly downregulates SATB2, resulting in the inhibition of GSC self-renewal and GBM growth, which can be rescued by the overexpression of SATB2. Importantly, pharmacological inhibition of USP10 by Wu-5 effectively suppresses tumor growth. These findings highlight the antagonistic roles of USP10 and DTX3L in the regulation of GBM malignancy and propose USP10 as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-67418-9
  5. Science. 2026 Jan 08. eady5532
    Mitochondrial control of fuel switching via carnitine biosynthesis.
    Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R P Verkerke, Alexander S Banks, Sheng Hui, Lijun Sun, Shingo Kajimura.
      Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.
    DOI:  https://doi.org/10.1126/science.ady5532
  6. NPJ Aging. 2026 Jan 03.
    Crosstalk between TGF-β and Wnt/β-catenin signaling drives fibrogenic and stem-like phenotypes in senescent MDA-MB-231 breast cancer cells.
    Mona El Samarji, Elissa Alam, Mariam Dakramanji, Mariam Bassam, Jana Santina, Marc Ayoub, Alex Aprahamian, Mohamad Rima.
      Genotoxic drugs used to treat cancer can trigger senescence, which contributes to chemotherapy resistance and tumor heterogeneity. However, the resulting cellular and molecular alterations following senescence remain poorly characterized. In this study, chemotherapy-induced senescence was triggered by etoposide in MDA-MB-231 breast cancer cells, and their fibrogenic potential, epithelial-to-mesenchymal transition (EMT), and stemness features were examined. In these cells, key mediators of fibrosis were significantly upregulated, suggesting a profibrotic potential involving TGF-β signaling. Etoposide also accentuated the mesenchymal phenotype of MDA-MB-231 cells and increased their motility. Additionally, nuclear β-catenin accumulation and upregulation of its EMT target genes were observed in senescent cells, alongside increased stemness markers, indicating a plastic cellular state involving Wnt/β-catenin signaling. Interestingly, pharmacological inhibition of the TGF-β/Wnt/β-catenin pathways reduced fibrosis, EMT, stemness marker expression, and cell migration, suggesting that these pathways are key regulators of these processes in senescent cells. These findings provide new insights into the molecular mechanisms driving chemotherapy-induced senescence and highlight these pathways as potential targets to alleviate resistance and aggressiveness in breast cancer.
    DOI:  https://doi.org/10.1038/s41514-025-00322-0
  7. Nature. 2026 Jan 07.
    Nutrient requirements of organ-specific metastasis in breast cancer.
    Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.
      Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
    DOI:  https://doi.org/10.1038/s41586-025-09898-9
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