bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–03–09
thirteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Ca2+ binding to Esyt modulates membrane contact site density in Drosophila photoreceptors.
  2. Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound.
  3. Dodging mitochondrial mislocalization.
  4. Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy.
  5. ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
  6. Mitochondrial dysfunction and carcinogenesis: The engagement of ion channels in cancer development.
  7. Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.
  8. Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma.
  9. Metabolic reprogramming in cancer and senescence.
  10. Large-scale CRISPRi screens link metabolic stress to glioblastoma chemoresistance.
  11. p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
  12. Pharmacological Modulation of Cellular Senescence: Implications for Breast Cancer Progression and Therapeutic Strategies.
  13. Targeting senescent cells to boost bone fracture healing.
  1. J Cell Biol. 2025 May 05. pii: e202407190. [Epub ahead of print]224(5):
    Ca2+ binding to Esyt modulates membrane contact site density in Drosophila photoreceptors.
    Vaisaly R Nath, Harini Krishnan, Shirish Mishra, Padinjat Raghu.
      Membrane contact sites (MCS) between the plasma membrane (PM) and endoplasmic reticulum (ER) regulate Ca2+ influx. However, the mechanisms by which cells modulate ER-PM MCS density are not understood, and the role of Ca2+, if any, in regulating these is unknown. We report that in Drosophila photoreceptors, MCS density is regulated by the Ca2+ channels, TRP and TRPL. Regulation of MCS density by Ca2+ is mediated by Drosophila extended synaptotagmin (dEsyt), a protein localized to ER-PM MCS and previously shown to regulate MCS density. We find that the Ca2+-binding activity of dEsyt is required for its function in vivo. dEsytCaBM, a Ca2+ non-binding mutant of dEsyt is unable to modulate MCS structure. Further, reconstitution of dEsyt null photoreceptors with dEsytCaBM is unable to rescue ER-PM MCS density and other key phenotypes. Thus, our data supports a role for Ca2+ binding to dEsyt in regulating ER-PM MCS density in photoreceptors thus tuning signal transduction during light-activated Ca2+ influx.
    DOI:  https://doi.org/10.1083/jcb.202407190
  2. Aging Cell. 2025 Mar 03. e70008
    Rejuvenation of Senescent Cells, In Vitro and In Vivo, by Low-Frequency Ultrasound.
    Sanjay K Kureel, Rosario Maroto, Maisha Aniqua, Simon Powell, Ekta Singh, Felix Margadant, Brandon Blair, Blake B Rasmussen, Michael P Sheetz.
      The presence of senescent cells causes age-related pathologies since their removal by genetic or pharmacological means, as well as possibly by exercise, improves outcomes in animal models. An alternative to depleting such cells would be to rejuvenate them to promote their return to a replicative state. Here we report that treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenates the cells for growth. Notably, there are 15 characteristics of senescent cells that are reversed by LFU, including senescence-associated secretory phenotype (SASP) plus decreased cell and organelle motility. There is also inhibition of β-galactosidase, p21, and p16 expression, telomere length is increased, while nuclear 5mC, H3K9me3, γH2AX, nuclear p53, ROS, and mitoSox levels are all restored to normal levels. Mechanistically, LFU causes Ca2+ entry and increased actin dynamics that precede dramatic increases in autophagy and an inhibition of mTORC1 signaling plus movement of Sirtuin1 from the nucleus to the cytoplasm. Repeated LFU treatments enable the expansion of primary cells and stem cells beyond normal replicative limits without altering phenotype. The rejuvenation process is enhanced by co-treatment with cytochalasin D, rapamycin, or Rho kinase inhibition but is inhibited by blocking Sirtuin1 or Piezo1 activity. Optimized LFU treatment parameters increased mouse lifespan and healthspan. These results indicate that mechanically induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.
    Keywords:  aging; autophagy; calcium signaling; low frequency ultrasound; rejuvenation; senescence
    DOI:  https://doi.org/10.1111/acel.70008
  3. Nat Rev Mol Cell Biol. 2025 Mar 06.
    Dodging mitochondrial mislocalization.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00840-5
  4. J Clin Invest. 2025 Mar 03. pii: e189519. [Epub ahead of print]135(5):
    Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy.
    Gemma L Carvill.
      Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.
    DOI:  https://doi.org/10.1172/JCI189519
  5. Nat Commun. 2025 Feb 28. 16(1): 2071
    ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
    Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li, Pingyu Liu.
      Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-57334-3
  6. Cell Calcium. 2025 Mar 04. pii: S0143-4160(25)00019-3. [Epub ahead of print]128 103010
    Mitochondrial dysfunction and carcinogenesis: The engagement of ion channels in cancer development.
    Gilnei Bruno da Silva, Geórgia de Carvalho Braga, Júlia Leão Batista Simões, Margarete Dulce Bagatini, Aniela Pinto Kempka.
      Mitochondria represent a fundamental structure for cellular homeostasis, controlling multiple conditions regarding energetic functions and cellular survival. To maintain these organelles functioning in ideal conditions, their membranes count with ion channels for different inorganic ions, which must be balanced to offer the proper function for both the organelle and the cell. However, studies have shown that other health conditions impair the activities of mitochondrial ion channels, including cancer. In this sense, the altered activities of potassium, calcium, and calcium-activated potassium channels are mainly linked with cancer development and cellular homeostasis alteration, demonstrating their role as pharmacological targets. With that in mind, scientists have found significant mitochondrial and cellular responses related to apoptosis and reduction of cellular survival from cells with modulated ion channels, indicating the potential of this possible therapy in carcinogenic contexts. Nonetheless, few studies still evaluate mitochondrial ion channel modulation as a treatment against cancer. Hence, more research must be conducted on this subject.
    Keywords:  Cancer; Ion channel; Mitochondria; Warburg effect
    DOI:  https://doi.org/10.1016/j.ceca.2025.103010
  7. Nat Commun. 2025 Mar 03. 16(1): 2135
    Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites.
    Ayenachew Bezawork-Geleta, Camille J Devereux, Stacey N Keenan, Jieqiong Lou, Ellie Cho, Shuai Nie, David P De Souza, Vinod K Narayana, Nicole A Siddall, Carlos H M Rodrigues, Stephanie Portelli, Tenghao Zheng, Hieu T Nim, Mirana Ramialison, Gary R Hime, Garron T Dodd, Elizabeth Hinde, David B Ascher, David A Stroud, Matthew J Watt.
      Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate fatty acid oxidation and adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria contact sites and their effects on biological processes are poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins at lipid droplet-mitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB). High resolution imaging confirms localization of this complex at the interface of lipid droplet-mitochondria-endoplasmic reticulum where it likely transfers fatty acids to enable β-oxidation. Deletion of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodeling of the cellular lipidome, and induction of lipotoxic stress. These findings were recapitulated in Esyt1 and Esyt2 deficient mice. Our study uncovers a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homeostasis, with implications for metabolic diseases and survival.
    DOI:  https://doi.org/10.1038/s41467-025-57405-5
  8. Sci Rep. 2025 Mar 04. 15(1): 7618
    Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma.
    Kent L Marshall, Murugesan Velayutham, Valery V Khramtsov, Alan Mizener, Christopher P Cifarelli.
      Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, with high recurrence rates and resistance to standard therapies. This study explores mitochondrial transplantation as a novel method to enhance the radiobiological effect (RBE) of ionizing radiation (IR) by increasing mitochondrial density in GBM cells, potentially boosting reactive oxygen species (ROS) production and promoting radiation-induced cell death. Using cell-penetrating peptides (CPPs), mitochondria were transplanted into GBM cell lines U3035 and U3046. Transplanted mitochondria were successfully incorporated into recipient cells, increasing mitochondrial density significantly. Mitochondrial chimeric cells demonstrated enhanced ROS generation post-irradiation, as evidenced by increased electron paramagnetic resonance (EPR) signal intensity and fluorescent ROS assays. The transplanted mitochondria retained functionality and viability for up to 14 days, with mitochondrial DNA (mtDNA) sequencing confirming high transfection and retention rates. Notably, mitochondrial transplantation was feasible in radiation-resistant GBM cells, suggesting potential clinical applicability. These findings support mitochondrial transplantation as a promising strategy to overcome therapeutic resistance in GBM by amplifying ROS-mediated cytotoxicity, warranting further investigation into its efficacy and mechanisms in vivo.
    Keywords:  Cell-penetrating peptide; EPR; Glioblastoma; Mitochondria; RBE; ROS; Radiation
    DOI:  https://doi.org/10.1038/s41598-025-91331-2
  9. MedComm (2020). 2025 Mar;6(3): e70055
    Metabolic reprogramming in cancer and senescence.
    Yuzhu Zhang, Jiaxi Tang, Can Jiang, Hanxi Yi, Shu Guang, Gang Yin, Maonan Wang.
      The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impact of key factors leading to cellular senescence on tumorigenesis. In addition, this review summarizes the current intervention strategies targeting nutrient sensing pathways, as well as the clinical cases of treating tumors targeting the characteristics of senescence with the existing nanodelivery research strategies. Finally, it also suggests sensible dietary habits for those who wish to combat aging. In conclusion, this review attempts to sort out the link between aging and metabolism and provide new ideas for cancer treatment.
    Keywords:  aging; metabolic reprogramming; mitochondrial dysfunction; signaling pathways; tumor
    DOI:  https://doi.org/10.1002/mco2.70055
  10. J Transl Med. 2025 Mar 06. 23(1): 289
    Large-scale CRISPRi screens link metabolic stress to glioblastoma chemoresistance.
    Xing Li, Wansong Zhang, Yitong Fang, Tianhu Sun, Jian Chen, Ruilin Tian.
       BACKGROUND: Glioblastoma (GBM) patients frequently develop resistance to temozolomide (TMZ), the standard chemotherapy. While targeting cancer metabolism shows promise, the relationship between metabolic perturbation and drug resistance remains poorly understood.
    METHODS: We performed high-throughput CRISPR interference screens in GBM cells to identify genes modulating TMZ sensitivity. Findings were validated using multiple GBM cell lines, patient-derived glioma stem cells, and clinical data. Molecular mechanisms were investigated through transcriptome analysis, metabolic profiling, and functional assays.
    RESULTS: We identified phosphoglycerate kinase 1 (PGK1) as a key determinant of TMZ sensitivity. Paradoxically, while PGK1 inhibition suppressed tumor growth, it enhanced TMZ resistance by inducing metabolic stress. This activated AMPK and HIF-1α pathways, leading to enhanced DNA damage repair through 53BP1. PGK1 expression levels correlated with TMZ sensitivity across multiple GBM models and patient samples.
    CONCLUSIONS: Our study reveals an unexpected link between metabolic stress and chemoresistance, demonstrating how metabolic adaptation can promote therapeutic resistance. These findings caution against single-agent metabolic targeting and suggest PGK1 as a potential biomarker for TMZ response in GBM.
    Keywords:   PGK1 ; CRISPR screening; DNA damage repair; Glioblastoma; Metabolic stress; Temozolomide resistance
    DOI:  https://doi.org/10.1186/s12967-025-06261-4
  11. Nat Commun. 2025 Mar 05. 16(1): 2229
    p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Shreeya Patel, Xue Lei, Adarsh Rajesh, Marcos G Teneche, Aaron P Havas, Armin Gandhi, Carolina Cano Macip, Jun Lyu, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Michael A LaPorta, Tianhui Liu, Nirmalya Dasgupta, Sha Li, Andrew Davis, Anatoly Korotkov, Erik Hultenius, Zichen Gao, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Andrei Seluanov, Vera Gorbunova, Susan M Kaech, Xiao Tian, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
    DOI:  https://doi.org/10.1038/s41467-025-57229-3
  12. Eur J Pharmacol. 2025 Mar 04. pii: S0014-2999(25)00229-8. [Epub ahead of print] 177475
    Pharmacological Modulation of Cellular Senescence: Implications for Breast Cancer Progression and Therapeutic Strategies.
    Jialing Xie, Xianlong Shu, Zilan-Xie, Jie Tang, Guo Wang.
      Senescence, defined by the cessation of cell proliferation, plays a critical and multifaceted role in breast cancer progression and treatment. Senescent cells produce senescence-associated secretory phenotypes (SASP) comprising inflammatory cytokines, chemokines, and small molecules, which actively shape the tumor microenvironment, influencing cancer development, progression, and metastasis. This review provides a comprehensive analysis of the types and origins of senescent cells in breast cancer, alongside their markers and detection methods. Special focus is placed on pharmacological strategies targeting senescence, including drugs that induce or inhibit senescence, their molecular mechanisms, and their roles in therapeutic outcomes when combined with chemotherapy and radiotherapy. By exploring these pharmacological interventions and their impact on breast cancer treatment, this review underscores the potential of senescence-targeting therapies to revolutionize breast cancer management.
    Keywords:  SASP; breast cancer; pharmacotherapy; senescence therapy; senotherapeutics
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177475
  13. J Clin Invest. 2024 Jun 17. pii: e181974. [Epub ahead of print]134(12):
    Targeting senescent cells to boost bone fracture healing.
    Lorenz C Hofbauer, Ulrike Baschant, Christine Hofbauer.
      Bone fracture healing is a complex process with distinct phases: the inflammatory phase, the soft and hard callus formation, and the remodeling phase. In older individuals, bone healing can be delayed or disturbed, leading to non-union fractures at worst. The initial healing phases require communication between immune cells and osteoprogenitor cells. However, senescence in these cell types impedes fracture healing by unknown mechanisms. In this issue of the JCI, Saul et al. showed that two distinct senescent p21-expressing cell populations, an osteochondroprogenitor cell and a neutrophil subpopulation, intrinsically impair fracture healing in mice irrespective of age. Genetic ablation of p21-positive cells accelerated fracture healing, while removal of a different senescent cell population, p16-positive cells, made no difference. Conceptually, this view of senescence in fracture healing with a spotlight on osteoimmune cross-talk provides a promising rationale for therapies to boost bone repair at all ages.
    DOI:  https://doi.org/10.1172/JCI181974
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