bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–10–05
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca2+ signals.
  2. Aging: the wound that never starts healing.
  3. Investigation of the heterogeneity of cancer cells using single cell Ca2+ profiling.
  4. Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
  5. Apelin in glioblastoma: A dual target for tumor and vascular intervention.
  6. Diabetes reshapes pancreatic cancer-associated endothelial niche by accelerating senescence.
  7. NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter.
  1. Br J Pharmacol. 2025 Oct 03.
    A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca2+ signals.
    Anna Lischnig, Yusuf C Erdoğan, Benjamin Gottschalk, Michael Gruber, Andrea Groselj-Strele, Sandra Burgstaller, Wolfgang F Graier, Roland Malli.
       BACKGROUND AND PURPOSE: The calcium ion (Ca2+) is a versatile cellular messenger regulating a variety of biological processes. Compounds modulating subcellular Ca2+ signals hold substantial pharmacological potential. Advances in fluorescent biosensors have revolutionised Ca2+ imaging. However, co-expression of targeted biosensors for simultaneous measurement of Ca2+ signals in multiple cellular compartments is still complicated by heterogeneous expression levels of the various sensors.
    EXPERIMENTAL APPROACH: We developed the ribosomal skipping-based quad-cistronic fluorescent biosensor system CARMEN, enabling high-content Ca2+ imaging across three compartments. CARMEN allows proportional co-expression of spectrally distinct Ca2+ biosensors: the near-infrared Ca2+ biosensor for the cytosol (NIR-GECO2G-NES), the green Ca2+ biosensor for mitochondria (CEPIA3mt) and the red Ca2+ biosensor for the endoplasmic reticulum (R-CEPIA1er), along with a Ca2+-insensitive blue fluorescent protein targeted to the nucleus (NLS-mTagBFP2), serving as a normalisation reference.
    KEY RESULTS: CARMEN allows spatiotemporal correlation of Ca2+ signals across the cytosol, endoplasmic reticulum and mitochondria, revealing distinct dynamics. We noted delayed mitochondrial Ca2+ uptake compared to the other compartments. We validated CARMEN across three cell types and tested two recently identified mitochondrial Ca2+ uniporter inhibitors (MCUis), MCUi4 and MCUi11, showcasing the potential of CARMEN for its application in pharmacological research. Our results show that while both MCUi4 and MCUi11 inhibited mitochondrial Ca2+ uptake in HeLa S3 cells, MCUi4 reduced cytosolic Ca2+ signals and oscillations, whereas MCUi11 had opposing effects.
    CONCLUSIONS AND IMPLICATIONS: CARMEN is a powerful tool for real-time, multiplexed analysis of compartment-specific Ca2+ signals, with the potential for automation in high-content drug screening.
    Keywords:  Ca2+ multiplexing; MCU inhibitors ; fluorescence microscopy; genetically encoded Ca2+ biosensors ; spatiotemporal Ca2+ imaging
    DOI:  https://doi.org/10.1111/bph.70211
  2. Nat Commun. 2025 Sep 30. 16(1): 8732
    Aging: the wound that never starts healing.
    Mikolaj Ogrodnik.
      Aging is a complex biological process leading to functional decline and disease susceptibility. This article proposes that chronic activation of tissue damage response mechanisms drives aging, with aged organs exhibiting features similar to those seen after acute injury, such as histolysis, inflammation, immune cell infiltration, accumulation of lipid droplets, and induction of cellular senescence. The overlap between injury and aging phenotypes is supported by evidence that interventions slowing aging often impair healing, and vice versa. This perspective offers a unifying framework to understand aging and suggests new directions for treating age-related diseases, cancer, and the aging process.
    DOI:  https://doi.org/10.1038/s41467-025-64462-3
  3. Cell Commun Signal. 2025 Oct 02. 23(1): 413
    Investigation of the heterogeneity of cancer cells using single cell Ca2+ profiling.
    Amélie E Bura, Camille Caussette, Maxime Guéguinou, Dorine Bellanger, Alison Robert, Mathilde Cancel, Margot Lacouette-Rata, Gaëlle Fromont, Christophe Vandier, Karine Mahéo, Thierry Brouard, David Crottès.
       BACKGROUND: Calcium (Ca2+) is an essential second messenger that controls numerous cellular functions. Characteristics of intracellular Ca2+ oscillations define Ca2+ signatures representatives of the phenotype of a cell. Oncogenic functions such as migration, proliferation or resistance to chemotherapy have been associated with aberrant Ca2+ fluxes. However, the identification of Ca2+ signatures representatives of the oncogenic properties of cancer cells remains to be addressed.
    METHODS: To characterize and investigate the heterogeneity of oncogenic Ca2+ signatures, we proposed an unbiased scalable method that combines single cell calcium imaging with graph-based unsupervised and artificial neural networks.
    RESULTS: From an initial dataset of 27,439 agonist-induced Ca2+ responses elicited in a panel of 16 prostate and colorectal cancer cell lines, we discriminate 26 clusters of Ca2+ responses using unbiased unsupervised clustering. From these clusters, we generate Ca2+ signatures for each cancer model allowing to functionally compare different cancer models. In parallel, we propose supervised neural network models predicting characteristics of a single cancer cell based on its profile of Ca2+ responses. We applied those methods to characterized a remodeling of Ca2+ signatures associated with acquired docetaxel resistance (12,911 cells) or in the course of the interaction of cancer cells with fibroblasts (34,676 cells). At single cell level, our supervised neural network succeeded to identify docetaxel-resistant cancer cells and to distinguish cancer cells from fibroblasts on the sole measure of agonist-induced Ca2+ response.
    CONCLUSIONS: Our method demonstrates the potential of Ca2+ profiling for discriminating cancer cells and predict their phenotypic characteristics at single cell level, and provides a framework for researchers to investigate the remodeling of the Ca2+ signature during cancer development.
    Keywords:  Cancer cells; Colorectal cancer; Docetaxel resistance; Graph-based unsupervised clustering; Predictive neural networks; Prostate cancer; Single cell calcium imaging
    DOI:  https://doi.org/10.1186/s12964-025-02417-3
  4. Cancer Res. 2025 Oct 01. OF1-OF3
    Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
    Désirée Schatton, Christian Frezza.
      Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3356
  5. Vascul Pharmacol. 2025 Sep 30. pii: S1537-1891(25)00087-4. [Epub ahead of print] 107548
    Apelin in glioblastoma: A dual target for tumor and vascular intervention.
    Gabriela E Wachholz, Karlijn van Loon, Arjan W Griffioen.
      Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults, marked by rapid progression, profound intratumoral heterogeneity and poor prognosis despite multimodal therapy. Current standard-of-care treatments, including maximal surgical resection followed by radiotherapy and temozolomide chemotherapy, offer only modest survival benefits, with most patients facing inevitable recurrence. A defining feature of GBM is its pronounced vascular proliferation, which supports tumor progression. This has spurred interest in targeting angiogenesis as a potential treatment approach. Apelin, a peptide involved in the regulation of angiogenesis and endothelial cell proliferation, has emerged as a key player in GBM pathogenesis. The Apelin/APJ signaling pathway is implicated in promoting tumor vascularization, invasiveness, and resistance to therapy, making it a promising therapeutic target. This review explores the role of Apelin/APJ pathway in GBM progression, focusing on its contribution to angiogenesis, as well as tumor growth and invasiveness. By integrating current findings, we aim to establish the rationale for targeting Apelin signaling as a novel therapeutic strategy in GBM, with the ultimate goal of overcoming treatment resistance and improving patient outcomes.
    Keywords:  Angiogenesis inhibition; Anti-angiogenic therapy; Apelin; Glioblastoma; Immunotherapy; Tumor vasculature
    DOI:  https://doi.org/10.1016/j.vph.2025.107548
  6. Nat Commun. 2025 Sep 30. 16(1): 8654
    Diabetes reshapes pancreatic cancer-associated endothelial niche by accelerating senescence.
    Yu-Wei Ling, Juan-Li Duan, Zi-Jian Jiang, Zhen Yang, Jing-Jing Liu, Ping Song, Zhi-Qiang Fang, Zhen-Sheng Yue, Fei He, Ke-Feng Dou, Lin Wang.
      Approximately half of pancreatic cancer patients present with comorbid diabetes. Diabetes is correlated with adverse prognostic outcomes in pancreatic cancer patients, but the underlying mechanism remains elusive. Here, we demonstrate that the cancer-associated endothelial niche is reshaped in the diabetic pancreatic tumor microenvironment and enhances the tumor-promoting capacity. Senescent endothelial cells expand in the diabetic tumor microenvironment and produce a potential senescence-associated secretory phenotype factor, i.e., INHBB. As a member of the TGF-β superfamily, INHBB promotes tumor progression and is regulated by Notch signaling. Pharmacological inhibition of INHBB receptors with bimagrumab effectively inhibited tumor progression in diabetic mice. Moreover, short-term bimagrumab treatment did not significantly decrease glucose levels in diabetic tumor-bearing mice. Combination treatment with metformin showed synergistic antitumor effects. In conclusion, our study identifies INHBB as a promising therapeutic target for pancreatic cancer with comorbid diabetes, laying the foundation for the development of individualized therapies for pancreatic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-025-63801-8
  7. EMBO J. 2025 Sep 29.
    NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter.
    Sharon Raju, Akshay Sharma, Sakshi Dahiya, Gyan Ranjan, Rajender K Motiani.
      Several autonomous mechanisms regulate protein expression, such as transcription, translation, post-translational modifications, and epigenetic changes. Rarely, these processes are controlled by the same molecular player with overlapping roles. Here, we reveal that transcription factor NFATc1 regulates both transcription and degradation of the Ca2+ channel Orai3 in a context-dependent manner. We demonstrate that NFATc1 drives Orai3 transcription in non-metastatic pancreatic cancer cells. In invasive and metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase. We show that MARCH8 physically interacts with Orai3 intracellular loop eventually resulting in its ubiquitination at the N-terminal. Mechanistically, the dichotomy in the regulation of Orai3 expression emerges from the differences in MARCH8 epigenetic landscape. We uncover that MARCH8 promoter is hyper-methylated in non-metastatic cells. Importantly, we demonstrate that MARCH8 restricts pancreatic cancer metastasis by targeting Orai3 degradation, thereby highlighting the pathophysiological importance of this signaling module. Taken together, we report a unique and clinically relevant scenario wherein the same transcription factor both enhances and curtails the expression of a target protein in cancer.
    Keywords:  MARCH8; NFATc1; Orai3; Transcription; Ubiquitination
    DOI:  https://doi.org/10.1038/s44318-025-00572-4
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒05 at 13:14.