bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–11–23
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. A new probe illuminates endo-lysosomal Ca2+ measurements: A role for vesicular IP3 receptors?
  2. Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice.
  3. Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
  4. Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.
  5. Update on VAP, a ubiquitous signpost for the ER.
  6. Succinate puts the brakes on de novo purine synthesis.
  7. Temozolomide-induced senescent glioblastoma cells acquire sensitivity to TRAIL death receptor 5-mediated apoptosis.
  8. Spatial patterns of glioblastoma.
  9. Age distinguishes breast cancer cellular and molecular profiles.
  1. J Cell Biol. 2025 Dec 01. pii: e202511020. [Epub ahead of print]224(12):
    A new probe illuminates endo-lysosomal Ca2+ measurements: A role for vesicular IP3 receptors?
    Anthony J Morgan.
      In this issue, Calvo et al. (https://doi.org/10.1083/jcb.202410094) report a new bioluminescent Ca2+ probe (ELGA) targeted to acidic endo-lysosomes (ELs) to permit selective and dynamic recording of endo-lysosomal Ca2+ uptake and release. Ca2+ was not only released by canonical EL channels but, surprisingly, by IP3 receptors.
    DOI:  https://doi.org/10.1083/jcb.202511020
  2. Cell Metab. 2025 Nov 20. pii: S1550-4131(25)00443-7. [Epub ahead of print]
    Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice.
    Masayoshi Suda, Selim Chaib, Larissa G P Langhi Prata, Yi Zhu, Utkarsh Tripathi, Karl H Paul, Allyson K Palmer, Tamar Pirtskhalava, Vagisha Kulshreshtha, Christina L Inman, Kurt O Johnson, Nino Giorgadze, Runqing Huang, Carolyn M Roos, Luisa F Leon-Sanchez, Jordan D Miller, Thomas White, Linshan Laux, Laura J Niedernhofer, Paul D Robbins, Sara Espinoza, Nicolas Musi, Sundeep Khosla, Stefan G Tullius, Tamar Tchkonia, James L Kirkland.
      Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (p16Ink4a-LOX-ATTAC mice) with Tie2-Cre mice (Tie2-Cre;p16Ink4a-LOX-ATTAC) to enable identification and inducible, selective elimination of p16Ink4a+ senescent endothelial cells. Targeted removal of senescent endothelial cells from obese Tie2-Cre;p16Ink4a-LOX-ATTAC mice attenuated the pro-inflammatory senescence-associated secretory phenotype and alleviated metabolic dysfunction. Conversely, transplanting senescent endothelial cells into lean mice caused adipose tissue inflammation and metabolic dysfunction. Consistent with these findings, the senolytic, fisetin, which targets senescent endothelial cells among other senescent cell types, reduced adipose tissue senescent endothelial cell abundance and improved glucose metabolism in obese mice or mice transplanted with senescent mouse endothelial cells. Our results indicate that specifically eliminating p16Ink4a+ senescent endothelial cells is a potential therapeutic strategy for metabolic disease.
    Keywords:  SASP factors; TNFα; cellular senescence; diabetes; endothelial cells; fisetin; glucose intolerance; obesity; p16(Ink4a); senolytics
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.009
  3. Nat Metab. 2025 Nov 20.
    Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
    Sarmistha Mukherjee, Ricardo A Velázquez Aponte, Caroline E Perry, Won Dong Lee, Kevin A Janssen, Marc Niere, Gabriel K Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W Frederick, Ryan B Gaspar, Khanh V Doan, James G Davis, Joshua D Rabinowitz, Douglas C Wallace, Nathaniel W Snyder, Shingo Kajimura, Xiaolu A Cambronne, Mathias Ziegler, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
    DOI:  https://doi.org/10.1038/s42255-025-01408-5
  4. Cancer Res. 2025 Nov 17.
    Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.
    Maria Dubisova, Klara Bohacova, Zuzana Nahacka, Daniel Kraus, Jaromir Novak, Sarka Dvorakova, Petra Brisudova, Natalie Danesova, Saba Selvi, Mariia Hrysiuk, Berwini B Endaya, Panagiotis Botsios, Dan-Diem Thi Le, Monika Novotna, Sona Vodenkova, Jaroslav Truksa, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Stepana Boukalova, Michael V Berridge, Renata Zobalova, Jiri Neuzil.
      Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer (HMT) to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. Here, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. While ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including pro-tumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSCs). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0737
  5. Biol Chem. 2025 Nov 21.
    Update on VAP, a ubiquitous signpost for the ER.
    Tim P Levine.
      The small protein family of VAMP-associated proteins (VAPs) have the unique position in cell biology as intracellular signposts for the Endoplasmic Reticulum (ER). VAP is recognised by a wide range of other proteins that use it to target the ER, either simply being recruited from the cytoplasm, or being recruited from separate organelles. The latter process makes VAP a component of many bridges between the ER and other compartments at membrane contact sites. The fundamental observations that identify VAP as the ER signpost have largely remained unchanged for over two decades. This review will describe how increased understanding of the special role of VAP in recent years has led to new discoveries: what constitutes the VAP family, how proteins bind to VAP, and which cellular functions connect to the ER using VAP. It will also describe the pitfalls that have led to difficulties determining how some proteins bind VAP and suggest some possibilities for future research.
    Keywords:  FFAT motif; cyclic AMP (cAMP); lipid transfer protein (LTP); non-vesicular transport; nucleolus; short linear motif (SLiM)
    DOI:  https://doi.org/10.1515/hsz-2025-0199
  6. Mol Cell. 2025 Nov 20. pii: S1097-2765(25)00861-5. [Epub ahead of print]85(22): 4109-4110
    Succinate puts the brakes on de novo purine synthesis.
    Timothy C Kenny, Kıvanç Birsoy.
      In this issue of Molecular Cell, Nengroo et al.1 report that the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is essential for de novo purine synthesis, revealing a previously unrecognized metabolic dependency in cancer that can be leveraged therapeutically.
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.020
  7. Med Oncol. 2025 Nov 18. 43(1): 4
    Temozolomide-induced senescent glioblastoma cells acquire sensitivity to TRAIL death receptor 5-mediated apoptosis.
    Alina A Isakova, Diana V Mazur, Nadezhda V Antipova, Irina N Druzhkova, Аrtem М Mozherov, Kirill S Krasnov, Roman S Fadeev, Mikhail P Kirpichnikov, Marine E Gasparian, Anne V Yagolovich.
      Therapy-induced senescence plays a crucial role in cancer treatment, evolving the resistance of malignant cells to therapeutic interventions. Therefore, the discovery of safe and effective senolytics may serve to develop new promising therapeutic options. Here we have revealed the enhanced apoptotic potential of DR5 receptor agonist, receptor-selective TRAIL variant DR5-B in temozolomide-induced senescent glioblastoma cell lines U87MG and T98G and primary tumor samples from patients with diagnosed glioblastoma. Senescence features were most pronounced in p53-proficient, MGMT-deficient U87MG cells, as demonstrated by enlarged cell and nuclei size, increased β-galactosidase activity, p21 expression and lipofuscin autofluorescence. This was accompanied by a metabolic shift towards glycolysis measured by fluorescence lifetime imaging (FLIM) of NADH, and upregulation of DR5, DcR1, DcR2 and cFLIP. As a result, a strong sensitization of U87MG cells to DR5-B-mediated apoptosis was observed after TMZ pre-treatment. However, neither was observed in p53-mutated, MGMT-proficient T98G cells. Differential gene expression analysis in TMZ-treated U87MG cells showed the activation of proinflammatory and proapoptotic signaling and downregulation of genes related to DNA metabolism and cell cycle. Two of three primary patient-derived glioblastoma samples tested acquired similar senescence features and were sensitized to DR5-B-mediated apoptosis by TMZ pre-treatment. These findings suggest that TMZ-induced senescence enhances glioblastoma cell sensitivity to DR5 receptor agonists. However, when developing strategies for senolytic antitumor therapy, the heterogeneous response of tumor cells to senescence induction should be taken into account.
    Keywords:  Apoptosis; DR5 receptor; Glioblastoma; Senescence; TRAIL
    DOI:  https://doi.org/10.1007/s12032-025-03130-4
  8. Cancer Cell. 2025 Nov 20. pii: S1535-6108(25)00489-1. [Epub ahead of print]
    Spatial patterns of glioblastoma.
    Toshiro Hara, Cong Ma.
      Glioblastoma features extensive gene expression heterogeneity and high lethality, yet the mechanisms underlying this heterogeneity and its link to clinical outcomes remain elusive. In this issue of Cancer Cell, Migliozzi et al. spatially profile glioblastoma specimens to uncover cellular mechanisms that govern the extent of the heterogeneity in malignant cells.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.013
  9. Nat Aging. 2025 Nov 17.
    Age distinguishes breast cancer cellular and molecular profiles.
      
    DOI:  https://doi.org/10.1038/s43587-025-01036-4
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