bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–09–14
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Ca2+ Fluxes across Membrane Contact Sites.
  2. Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
  3. An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
  4. Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress.
  5. Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
  6. Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
  7. Role of Notch and its oncogenic signaling crosstalk in glioma and glioma stem cells.
  1. Cold Spring Harb Perspect Biol. 2025 Sep 09. pii: a041765. [Epub ahead of print]
    Ca2+ Fluxes across Membrane Contact Sites.
    Lucia Barazzuol, Marisa Brini, Tito Calì.
      The calcium ion (Ca2+) is a pivotal second messenger orchestrating diverse cellular functions, including metabolism, signaling, and apoptosis. Membrane contact sites (MCSs) are critical hubs for Ca2+ exchange, enabling rapid and localized signaling across cell compartments. Well-characterized interfaces, such as those between the endoplasmic reticulum (ER) and mitochondria and ER-plasma membrane (PM), mediate Ca2+ flux through specialized channels. Less understood, yet significant, contacts involving Golgi, lysosomes, peroxisomes, and the nucleus further expand the landscape of intracellular Ca2+ signaling. These organelles are engaged in Ca2+ homeostasis mainly through their MCS, but the molecular players and the mechanisms regulating the process of Ca2+ transfer remain incompletely elucidated. This review provides a comprehensive overview of Ca2+ signaling across diverse MCS, emphasizing understudied organelles and the need for further investigation to uncover novel therapeutic opportunities.
    DOI:  https://doi.org/10.1101/cshperspect.a041765
  2. Autophagy. 2025 Sep 13.
    Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
    Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.
    Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria
    DOI:  https://doi.org/10.1080/15548627.2025.2561073
  3. Nat Metab. 2025 Sep 08.
    An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Rachel 'Rae' J House, Althea Waldhart, Kelly H Sokol, Samuel R Daniels, Cameron J Lee, Joseph Longo, Amy Johnson, Vincent J Sartori, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53-/- pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1038/s42255-025-01366-y
  4. Geroscience. 2025 Sep 11.
    Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress.
    Grant R Laskin, Laís R Perazza, Ted G Graber, Baylah R Mazonson, Yuhoung J Kim, Laura J Verdi, LaDora V Thompson.
      Frailty is a clinical syndrome marked by diminished physiological reserve and function. While skeletal muscle dysfunction is central to frailty, most preclinical models focus on basal function and place less emphasis on physiological stress responses. Here, we examined the influence of increased indices of frailty on skeletal muscle resistance and resilience using a physiologically relevant model of downhill running stress. Aged female C57BL/6JN mice (n = 47; > 17 months) were stratified into Low (≤ 1 frailty markers) or High (≥ 2 frailty markers) groups based on their number of positive frailty markers. Mice were subsequently randomized to undergo two bouts of downhill running or remain cage sedentary. Twenty-four hours later, contractile function was assessed ex vivo in the extensor digitorum longus (EDL) and soleus muscles. RNA was extracted from the gastrocnemius of randomly selected samples and analyzed by RNA sequencing. Despite comparable specific tetanic force, High frailty marked mice exhibited greater fatiguability and impaired recovery kinetics in the EDL following running stress. RNA sequencing revealed divergent transcriptional signatures between mice in Low and High frailty marked groups in response to running, including upregulation of mitochondrial bioenergetic and complex assembly pathways in Low group mice and downregulation in High group mice. These data demonstrate that downhill running stress unmasks latent impairments with frailty in skeletal muscle, and that mitochondrial dysfunction and/or redox imbalance may be potential contributors to reduced muscle resilience. Overall, our results emphasize the importance of incorporating physiological stress paradigms to uncover frailty-associated muscle impairments that are not apparent under basal conditions.
    Keywords:  Frailty; Mitochondrial dysfunction; Muscle contractility; Stress resilience
    DOI:  https://doi.org/10.1007/s11357-025-01856-7
  5. Nat Aging. 2025 Sep 09.
    Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
    Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E Janssens, Riekelt H Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A Bohr, Charalampos Tzoulis, David A Sinclair, Evandro Fei Fang.
      Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.
    DOI:  https://doi.org/10.1038/s43587-025-00947-6
  6. Exp Eye Res. 2025 Sep 08. pii: S0014-4835(25)00403-8. [Epub ahead of print] 110632
    Imbalanced mitochondrial homeostasis in ocular diseases: unique pathogenesis and targeted therapy.
    Hetong Sun, Bin Li, Yu Gu, Fei Li, Guohu Di, Peng Chen.
      Mitochondria play a crucial role in energy production and are intimately associated with ocular function. Mitochondrial dysfunction can trigger oxidative stress and inflammation, adversely affecting key ocular structures such as the lacrimal gland, lens, retina, and trabecular meshwork. This dysfunction may compromise the barrier properties of the trabecular meshwork, impeding aqueous humour outflow, elevating intraocular pressure, and resulting in optic nerve damage and primary open-angle glaucoma. Additionally, impaired mitochondrial homeostasis can contribute to dry eye, cataracts, and age-related macular degeneration (AMD) by disrupting the function of the lacrimal gland, lens, and macula. Imbalanced mitochondrial homeostasis primarily involves four pathological features: disruption of mitochondrial quality control, mitochondrial damage (inducing inflammation), excessive production of mitochondrial reactive oxygen species (ROS) (initiating oxidative stress), and disturbances in mitochondrial calcium (Ca2+) homeostasis. Oxidative stress and inflammation are central mechanisms of cellular injury. Pharmacological strategies aimed at reducing excessive ROS, restoring redox balance, and mitigating oxidative and inflammatory damage show therapeutic promise. Moreover, enhancing mitochondrial function through pharmacological agents, replacing damaged mitochondria, and promoting mitochondrial rejuvenation represent emerging treatment avenues. This review explores the relationship between mitochondrial dysfunction and ocular diseases such as dry eye, glaucoma, cataracts, and AMD, with a focus on associated mechanisms and potential therapeutic interventions.
    Keywords:  AMD; Cataracts; Dry eye; Glaucoma; Mitochondrial Dysfunction; Oxidative Stress; Targeted Therapy
    DOI:  https://doi.org/10.1016/j.exer.2025.110632
  7. Gene. 2025 Sep 09. pii: S0378-1119(25)00550-5. [Epub ahead of print] 149761
    Role of Notch and its oncogenic signaling crosstalk in glioma and glioma stem cells.
    Rajveer Sidhu, Shanchun Guo, Mingli Liu.
      Notch signaling (NS) is one of the primary regulators of Glioblastoma (GBM), which shapes tumour growth and evolution while protecting against drug treatments. Notch signaling enables Glioma stem cell (GSC) preservation in tumours, enhancing their diversity, and increasing tumour strength and resistance to treatment. Notch signaling keeps cancer cells growing and active through its ability to halt cell development while maintaining links with critical tumour pathways Wnt/β-catenin, PI3K/AKT, NF-kB, Hedgehog, and TGF-β. When signaling molecules communicate, they develop a strong system that enables tumour cells to survive longer and establish new blood vessels while resisting immune defenses and treatments. Developing treatments consisting of γ-secretase inhibitors, antibodies, and small molecule inhibitors show better outcomes when combined with other pathway-targeting approaches. Notch signaling may promote or inhibit cancer cell proliferation; it is crucial to detect unique biomarkers for each patient before developing individualized therapy regimens. The treatment of Notch-dependent tumours with PI3K/AKT or TGF-β inhibitors helps reduce resistance to therapy. The development of molecular techniques and single-cell analysis enables us to understand Notch signaling better for inventing treatment options specific to clinical settings. These approaches could be combined to improve the quality of life and speed up the recovery process for GBM patients. Notch signaling presents difficulties and possibilities that can guide new treatment options for GBM.
    Keywords:  Glioblastoma; Notch Signaling; Signaling interaction; Tumor Heterogenicity; and Glioma Stem cells
    DOI:  https://doi.org/10.1016/j.gene.2025.149761
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