bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–06–22
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor



  1. J Physiol. 2025 Jun 15.
      
    Keywords:  circadian rhythm; energy; mitochondria
    DOI:  https://doi.org/10.1113/JP289058
  2. Am J Physiol Cell Physiol. 2025 Jun 16.
      Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated expression of markers of fibrosis (Col1a1, MMP2 and MMP9) and inflammation (IL-6, MCP1, and CXCL12). In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.
    Keywords:  Drp1; Mitochondrial Dynamics; Muscular Dystrophy; lipid peroxidation; mitochondria dynamics; muscle; muscular dystrophy
    DOI:  https://doi.org/10.1152/ajpcell.01009.2024
  3. Nat Cell Biol. 2025 Jun;27(6): 902-917
      The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.
    DOI:  https://doi.org/10.1038/s41556-025-01668-z
  4. Cancer Cell. 2025 Jun 10. pii: S1535-6108(25)00224-7. [Epub ahead of print]
      Cellular senescence is a state of stable cell-cycle arrest induced by various intrinsic and extrinsic stressors, serving as a protective mechanism to prevent the proliferation of damaged cells. While this process is crucial for tissue homeostasis and tumor suppression, the progressive accumulation of senescent cells (SnCs) over time is implicated in age-related pathologies, including immune dysfunction and cancer. In oncology, senescence plays a paradoxical role: it can inhibit tumor development by halting the growth of potentially malignant cells, yet it may also facilitate tumor progression through the senescence-associated secretory phenotype (SASP). This review explores the defining features of senescence in cancer, its complex interactions with tumor cells, the stroma, and the immune system, and its context-dependent outcomes. We also discuss current and emerging therapeutic strategies that target SnCs-either by inducing or eliminating them-as well as AI-driven approaches for their detection and characterization in cancer.
    Keywords:  AI-approaches for senescence; PICS; SASP modulators; cancer; hallmarks of senescence; oncogene-induced senescence; prosenescence; senescence; senescence immune system; senescence in tumor microenvironment; senolytics; senomorphic; therapy-induced senescence
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.015
  5. Cell Mol Life Sci. 2025 Jun 14. 82(1): 238
      Homeostatic calcium ion (Ca2+) fluxes between the endoplasmic reticulum, cytosol, and extracellular space occur not only in response to cell stimulation but also in unstimulated cells. Using murine astrocytes as a model, we asked whether there is a signaling function of these resting Ca2+ fluxes. The data showed that endoplasmic reticulum (ER) Ca²⁺ depletion, induced by sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition, resulted to prolonged Ca²⁺ influx and mitochondrial fragmentation within 10 to 30 min. This mitochondrial fragmentation could be prevented in Ca2+-free medium or by inhibiting store-operated Ca2+ entry (SOCE). Similarly, attenuation of STIM proteins, which are vital ER Ca2+ sensors, protected mitochondrial morphology. On the molecular level, ER Ca2+ depletion, achieved either by removing extracellular Ca2+ or through acute SERCA inhibition, led to changes in gene expression of about 13% and 41% of the transcriptome within an hour, respectively. Transcriptome changes were associated with universal biological processes such as transcription, differentiation, or cell stress. Strong increase in expression was observed for the transcription factor ATF4, which is under control of the kinase PERK (EIF2AK3), a key protein involved in ER stress. Corroborating these findings, PERK was rapidly phosphorylated in Ca2+-free medium or after acute pharmacological inhibition of SOCE. In summary, resting, homeostatic Ca2+ fluxes prevent immediate-early cell stress and transcriptional reprogramming.
    Keywords:  Calcium signaling; ER calcium; ER calcium leak; Mitochondrial fragmentation; Resting calcium fluxes; Store-operated calcium entry; Transcriptome changes
    DOI:  https://doi.org/10.1007/s00018-025-05745-2
  6. Medicine (Baltimore). 2025 Jun 13. 104(24): e42886
      The tumor microenvironment (TME) significantly influences tumor development, progression, and clinical outcomes. Therapy-induced cellular senescence is a fundamental process affecting the microenvironment. This review summarizes the characteristics of therapy-induced cellular senescence, its beneficial and detrimental effects on the TME, and the underlying mechanisms contributing to its dual effects. It further elaborates on optimizing the beneficial aspects of therapy-induced cellular senescence while concomitantly mitigating its adverse effects in the treatment of tumors and prevention of recurrence. Finally, potential interventions, including antiaging drug therapies, senescence inducers, senescence clearance agents, and inhibition of adverse senescence-associated secretory phenotype (SASP) production were explored to inhibit the harmful SASP induced by therapy, with the aim of limiting the production of detrimental SASP in the TME, thereby reducing the risk of tumor recurrence.
    Keywords:  cancer; cellular senescence; senescence-associated secretory phenotype; therapy-induced senescence; tumor microenvironment
    DOI:  https://doi.org/10.1097/MD.0000000000042886
  7. Expert Rev Anticancer Ther. 2025 Jun 20. 1-5
      
    Keywords:  Carnivore diet; evidence; ketone bodies; ketosis; skepticism
    DOI:  https://doi.org/10.1080/14737140.2025.2522936
  8. Aging Cell. 2025 Jun 18. e70127
      The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.
    Keywords:  aging; isotope labeling; metabolomics; proteomics; rheo‐morphology; senescence
    DOI:  https://doi.org/10.1111/acel.70127
  9. Nature. 2025 Jun 16.
      
    Keywords:  Brain; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01898-z
  10. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  11. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  12. Cold Spring Harb Perspect Biol. 2025 Jun 16. pii: a041767. [Epub ahead of print]
      Calcium signaling is a key controller of numerous cellular events and is intricately linked to many processes that are critical pathways in cancer progression. This review revisits the calcium signaling toolkit in cancer, with a focus on calcium regulation of processes that go beyond the originally defined "classic" hallmarks of cancer such as those associated with proliferation, metastasis, and resistance to cell death pathways. We will consider calcium signaling in the context of the more recently proposed hallmarks of cancer, emerging hallmarks, and cancer-enabling characteristics. This broader examination of calcium signaling and its toolkit members will encompass processes such as metabolic reprogramming, evasion of immune destruction, cellular phenotypic plasticity, senescence, genome instability, and nonmutational epigenetic reprogramming. These cancer features and their interactions with calcium signaling will frequently be analyzed through the lenses of therapy resistance and the complexities of the tumor microenvironment.
    DOI:  https://doi.org/10.1101/cshperspect.a041767
  13. Nature. 2025 Jun;642(8068): 563-565
      
    Keywords:  Ageing; Brain
    DOI:  https://doi.org/10.1038/d41586-025-01886-3
  14. Semin Cancer Biol. 2025 Jun 11. pii: S1044-579X(25)00088-4. [Epub ahead of print]114 60-72
      Cellular senescence, described as a mechanism of irreversible cell cycle arrest, has emerged as a complex and multifaceted process with significant implications in cancer biology, particularly in pancreatic ductal adenocarcinoma (PDAC). This literature review aims to explore the intricate role of senescence in PDAC, focusing on its dual nature during tumorigenesis, in addition to therapy resistance, and its potential as a therapeutic target. Senescence escape was found to play a crucial role in PDAC progression, prompting the development of various pro-senescence therapies. However, recent studies have revealed a paradoxical aspect of the senescence-associated secretory phenotype, revealing its pro-tumorigenic effects and contribution to immune evasion in PDAC. By integrating insights from recent molecular studies, this review synthesizes current knowledge on the role of senescence in PDAC tumorigenesis and chemoresistance, with an emphasis on the emerging role of the tumor microenvironment and explores current and promising avenues for future research and potential therapeutic interventions.
    Keywords:  Chemoresistance; Hypoxia; Metabolism; Oncogene-induced senescence; Pancreatic ductal adenocarcinoma; Senescence; Senescence-associated secretory phenotype; Stroma; Therapy-induced senescence; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2025.06.007