bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024‒03‒24
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Plasma membrane damage is a new trigger of cellular senescence.
  2. Metformin alleviates junctional epithelium senescence via the AMPK/SIRT1/autophagy pathway in periodontitis induced by hyperglycemia.
  3. Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment.
  4. Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
  5. YAP upregulates AMPKα1 to induce cancer cell senescence.
  6. Biology of Stress Responses in Aging.
  7. Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.
  1. Trends Cell Biol. 2024 Mar 15. pii: S0962-8924(24)00051-5. [Epub ahead of print]
    Plasma membrane damage is a new trigger of cellular senescence.
    Nadine Martin, Céline Margand, David Bernard.
      By blocking proliferation and inducing a secretory phenotype, cellular senescence has beneficial and deleterious effects, the latter being linked to aging. Suda et al. recently reported that plasma membrane (PM) damage (PMD) triggers senescence, suggesting that PMD inducers promote senescence and that the PMD repair machinery can regulate it.
    Keywords:  ESCRT; aging; calcium; cellular senescence; plasma membrane damage
    DOI:  https://doi.org/10.1016/j.tcb.2024.03.002
  2. Heliyon. 2024 Mar 30. 10(6): e27478
    Metformin alleviates junctional epithelium senescence via the AMPK/SIRT1/autophagy pathway in periodontitis induced by hyperglycemia.
    Xiaoyuan Ye, Yumin Wang, Yanying Tian, Ruonan Bi, Mingyue Li, Chunyan Yang, Li Zhang, Yuguang Gao.
      The junctional epithelium (JE) serves a crucial protective role in the periodontium. High glucose-related aging results in accelerated barrier dysfunction of the gingival epithelium, which may be associated with diabetic periodontitis. Metformin, an oral hypoglycemic therapeutic, has been proposed as a anti-aging agent. This study aimed to clarify the effect of metformin on diabetic periodontitis and explore its mechanism in ameliorating senescence of JE during hyperglycemia. The db/db mice was used as a diabetic model mice and alterations in the periodontium were observed by hematoxylin-eosin staining and immunohistochemistry. An ameloblast-like cell line (ALC) was cultured with high glucose to induce senescence. Cellular senescence and oxidative stress were evaluated by SA-β-gal staining and Intracellular reactive oxygen species (ROS) levels. Senescence biomarkers, P21 and P53, and autophagy markers, LC3-II/LC3-I, were measured by western blotting and quantitative real-time PCR. To construct a stable SIRT1 (Sirtuin 1) overexpression cell line, we transfected ALCs with lentiviral vectors overexpressing the mouse SIRT1 gene. Cellular senescence was increased in the JE of db/db mice and the periodontium was destroyed, which could be alleviated by metformin. Moreover, oxidative stress and cellular senescence in a high glucose environment were reduced by metformin in in-vitro assays. The autophagy inhibitor 3-MA and SIRT1 inhibitor EX-527 could dampen the effects of metformin. Overexpression of SIRT1 resulted in increased autophagy and decreased oxidative stress and cellular senescence. Meanwhile, AMPK (AMP-activated protein kinase) inhibition reversed the anti-senescence effects of metformin. Overall, these results suggest that metformin alleviates periodontal damage in db/db mice and cellular senescence in ALCs under high glucose conditions via the AMPK/SIRT1/autophagy pathway.
    Keywords:  Hyperglycemia; Junctional epithelium; Metformin; Oxidative stress; Periodontitis; Senescence
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e27478
  3. Nat Commun. 2024 Mar 18. 15(1): 2435
    Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment.
    Damien Maggiorani, Oanh Le, Véronique Lisi, Séverine Landais, Gaël Moquin-Beaudry, Vincent Philippe Lavallée, Hélène Decaluwe, Christian Beauséjour.
      The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-024-46769-9
  4. Life Sci. 2024 Mar 14. pii: S0024-3205(24)00164-4. [Epub ahead of print]344 122575
    Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
    Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.
    Keywords:  Aging; Cardiovascular disease; Mitochondria; Mitochondrial dynamics; Obesity
    DOI:  https://doi.org/10.1016/j.lfs.2024.122575
  5. Int J Biochem Cell Biol. 2024 Mar 16. pii: S1357-2725(24)00050-5. [Epub ahead of print] 106559
    YAP upregulates AMPKα1 to induce cancer cell senescence.
    Yongtong Zhan, Guihao Wu, Xuhong Fan, Ze Fu, Yue Ni, Beini Sun, Hongce Chen, Tongsheng Chen, Xiaoping Wang.
      Yes-associated protein (YAP)-a major effector protein of the Hippo pathway- regulates cell proliferation, differentiation, apoptosis, and senescence. Amp-activated protein kinase (AMPK) is a key sensor that monitors cellular nutrient supply and energy status. Although YAP and AMPK are considered to regulate cellular senescence, it is still unclear whether AMPK is involved in YAP-regulated cellular senescence. Here, we found that YAP promoted AMPKα1 aggregation and localization around mitochondria by co-transfecting CFP-YAP and YFP-AMPKα1 plasmids. Subsequent live cell fluorescence resonance energy transfer (FRET) assay did not exhibit direct interaction between YAP and AMPKα1. FRET, Co-immunoprecipitation, and western blot experiments revealed that YAP directly bound to TEAD, enhancing the expression of AMPKα1 and p-AMPKα. Treatment with verteporfin inhibited YAP's binding to TEAD and reversed the elevated expression of AMPKα1 in the cells overexpressing CFP-YAP. Verteporfin also reduced the proportion of AMPKα1 puncta in the cells co-expressing CFP-YAP and YFP-AMPKα1. In addition, the AMPKα1 puncta were demonstrated to inhibit cell viability, autophagy, and proliferation, and ultimately promote cell senescence. In conclusion, YAP binds to TEAD to upregulate AMPKα1 and promotes the formation of AMPKα1 puncta around mitochondria under the condition of co-expression of CFP-YAP and YFP-AMPKα1, in which AMPKα1 puncta lead to cellular senescence.
    Keywords:  AMPKα1; TEAD; YAP; senescence
    DOI:  https://doi.org/10.1016/j.biocel.2024.106559
  6. Aging Biol. 2023 ;pii: 20230002. [Epub ahead of print]1
    Biology of Stress Responses in Aging.
    Manolis Maragkakis, Sulochan Malla, Maria Hatzoglou, Aleksandra Trifunovic, Adam B Glick, Toren Finkel, Valter D Longo, Susmita Kaushik, Pura Muñoz-Cánoves, Gordon J Lithgow, Nirinjini Naidoo, Lauren N Booth, Matthew J Payea, Allison B Herman, Rafael de Cabo, David M Wilson, Luigi Ferrucci, Myriam Gorospe.
      On April 28th, 2022, a group of scientific leaders gathered virtually to discuss molecular and cellular mechanisms of responses to stress. Conditions of acute, high-intensity stress are well documented to induce a series of adaptive responses that aim to promote survival until the stress has dissipated and then guide recovery. However, high-intensity or persistent stress that goes beyond the cell's compensatory capacity are countered with resilience strategies that are not completely understood. These adaptative strategies, which are an essential component of the study of aging biology, were the theme of the meeting. Specific topics discussed included mechanisms of proteostasis, such as the unfolded protein response (UPR) and the integrated stress response (ISR), as well as mitochondrial stress and lysosomal stress responses. Attention was also given to regulatory mechanisms and associated biological processes linked to age-related conditions, such as muscle loss and regeneration, cancer, senescence, sleep quality, and degenerative disease, with a general focus on the relevance of stress responses to frailty. We summarize the concepts and potential future directions that emerged from the discussion and highlight their relevance to the study of aging and age-related chronic diseases.
    DOI:  https://doi.org/10.59368/agingbio.20230001
  7. Cytotherapy. 2024 Mar 04. pii: S1465-3249(24)00087-2. [Epub ahead of print]
    Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.
    Omer Faruk Taner, Oner Ulger, Simay Ersahin, Nesrin Tan Baser, Onur Genc, Gokhan Burcin Kubat.
      BACKGROUND AIMS: Wound healing is a multistage process that requires a concerted effort of various cell types. The intricate processes involved in the healing of wounds result in high energy requirements. Furthermore, mitochondria play a crucial role in the healing process because of their involvement in neo angiogenesis, growth factor synthesis, and cell differentiation. It is unclear how mitochondria transplantation, a promising new approach, influences wound healing.METHODS: In this study, healthy autologous mitochondria obtained from skeletal muscle were injected into chronic pressure wounds as an intervention to promote wound healing.
    RESULTS: Mitochondrial transplantation accelerated wound healing by reducing wound size, increasing granulation tissue, and hastening epithelialization.
    CONCLUSIONS: This study is the first to demonstrate the therapeutic efficacy of mitochondrial transplantation in wound healing.
    Keywords:  chronic wounds; mitochondrial transplantation; skeletal muscle; wound healing
    DOI:  https://doi.org/10.1016/j.jcyt.2024.02.027
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