bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–07–27
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
  2. Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca2+ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.
  3. Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence.
  4. SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms.
  5. Ageing stem cells in the knees drive arthritis damage.
  6. Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.
  7. People's brains aged faster during the COVID pandemic - even the uninfected.
  8. Tunneling nanotubes between glioblastoma cells and T cells and hijack of mitochondria.
  1. Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]
    Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
    Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.
      Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-7042684/v1
  2. Adv Sci (Weinh). 2025 Jul 25. e15313
    Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 Ca2+ Crosstalk at Lysosome-ER MCSs Leading to Lethal Depleting of ER Calcium.
    Meng-Yuan Zhu, Yong-Jian Guo, Yu-Qi Zhu, Hong-Zheng Wang, Hai-di Wang, Hong-Yu Chen, Yue-Xin Jiang, Hui Li, Hui Hui.
      Inter-organellar signaling linkages in oncology are increasingly elucidated. However, the impact of lysosome-endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW-213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome-ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca2+-induced Ca2+ release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress-induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML-specific mechanisms when overexpressed. Subsequent studies using BALB/c xenograft models with wild-type and LIMP2-knockout THP1 cells, along with ICR mice toxicity models, confirmed LW-213's significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal-ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW-213 in managing tumor cell fate through modulating organellar interactions.
    Keywords:  ERS; LIMP2; calcium crosstalk; lysosomal dynamics; membrane contact site; organelle interaction
    DOI:  https://doi.org/10.1002/advs.202415313
  3. Cell Rep. 2025 Jul 17. pii: S2211-1247(25)00797-1. [Epub ahead of print]44(8): 116026
    Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence.
    Sung-Jen Wei, Joseph Schell, Wei Qian, Martin Silguero, Agne Baseviciene, Wan Hsi Chen, Rolando Trevino, E Sandra Chocron, Meredith M Ogle, Mahboubeh Varmazyad, Gloria M Martinez, Diego Cruz, Brandon Lorenzana, Felix F Dong, Haiyan Jiang, Alia Nazarullah, Robert A Beardsley, Kumar Sharma, Jenny Chang, Erin Munkácsy, Nobuo Horikoshi, David Gius.
      While a ketogenic diet (KD) can improve certain health parameters, evidence from murine and clinical studies suggests that these effects may be dependent on multiple variables. One understudied variable is the role of sex in the response to a KD. Here, we show that a KD-induced increase in p53, p21, and cellular senescence is only observed in male mice, except when they are given estrogen, and in female mice administered tamoxifen. Male, but not female, mice on a KD exhibit an increase in markers of oxidative stress and acetylation of mitochondrial proteins, including manganese superoxide dismutase (MnSOD). Notably, the increases in p53, p21, cellular senescence, MnSOD acetylation, and oxidative stress in male mice on a KD were all prevented by estrogen treatment. In addition, several established antioxidants and an MnSOD chemical mimetic also prevented KD-induced cellular senescence. These results suggest sex specificity in the effects of a KD, with important clinical implications.
    Keywords:  CP: Metabolism; MnSOD; SOD2; acetylation; antioxidant; cellular senescence; estrogen; ketogenic diet; oxidative stress; sex difference
    DOI:  https://doi.org/10.1016/j.celrep.2025.116026
  4. bioRxiv. 2024 Dec 22. pii: 2024.12.21.629928. [Epub ahead of print]
    SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms.
    Euxhen Hasanaj, Delphine Beaulieu, Cankun Wang, Qianjiang Hu, Marta Bueno, John C Sembrat, Ricardo H Pineda, Maria Camila Melo-Narvaez, Nayra Cardenes, Zhao Yanwu, Zhang Yingze, Robert Lafyatis, Alison Morris, Ana Mora, Mauricio Rojas, Dongmei Li, Irfan Rahman, Gloria S Pryhuber, Mareike Lehmann, Jonathan Alder, Aditi Gurkar, Toren Finkel, Qin Ma, Barnabás Póczos, Ziv Bar-Joseph, Oliver Eickelberg, Melanie Königshoff.
      Cellular senescence is a major hallmark of aging. Senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors including DNA damage, oxidative stress, or nutrient deprivation. While senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescence in healthy aged tissues represents a major challenge to studying senescence in a given organ, including the human lung. To overcome this limitation, we developed a Positive-Unlabeled (PU) learning framework to generate a comprehensive senescence marker gene list in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type specific senescence signatures in distinct lung cell populations upon aging and environmental exposures. Our study presents the first comprehensive analysis of senescent cells in the healthy aging lung and uncovers cell-specific gene signatures of senescence, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.
    DOI:  https://doi.org/10.1101/2024.12.21.629928
  5. Nature. 2025 Jul 23.
    Ageing stem cells in the knees drive arthritis damage.
      
    Keywords:  Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-02309-z
  6. Metabolites. 2025 Jul 11. pii: 472. [Epub ahead of print]15(7):
    Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.
    Danlin Zhu, Lian Wang, Haoyang Gao, Ze Wang, Ke Li, Xiaotong Ma, Linlin Zhao, Weihua Xiao.
      Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood. Methods: In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results: Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB-related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved. Conclusions: This study offers preliminary insights into how aerobic exercise may modulate mitochondrial quality control and β-HB-associated signaling pathways during aging.
    Keywords:  Sarcopenia; aerobic exercise; mitochondrial quality control; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo15070472
  7. Nature. 2025 Jul 22.
    People's brains aged faster during the COVID pandemic - even the uninfected.
    Gemma Conroy.
      
    Keywords:  Ageing; Brain; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-025-02313-3
  8. J Neurooncol. 2025 Jul 21.
    Tunneling nanotubes between glioblastoma cells and T cells and hijack of mitochondria.
    Yanamandra Venkataratnam, Victor Mukherjee, Nikhil Rai, Mahesh Mahalingaswamy, Diksha Shandilya, Subhas Konar, Nandeesh Bevinahalli Nanjegowda, Girish Waghmare, Nandakumar Dalavaikodihalli Nanjaiah.
       PURPOSE: Glioblastoma is a highly aggressive and invasive brain tumor that can interact dynamically with its surrounding tumor microenvironment, including resident and infiltrating-immune cells. These interactions largely govern glioblastoma progression and resistance to therapy. Glioblastoma cells can actively modulate immune cell functions, either by inhibiting immune responses or reprogramming immune cells. This study explores the dynamic interaction between glioblastoma cells and T cells.
    METHODS: The connections between glioblastoma cells and T cells were analyzed by immunohistochemistry, immunofluorescence and scanning electron microscopy. Inhibition of tunneling nanotubes (TNTs) between glioblastoma cells and T cells was performed using carbenoxolone. Fluorogenic probes were used for mitochondrial membrane potential and reactive oxygen species (ROS) in mitochondria, glioblastoma cells and T cells after co-culture. Viability and LAG-3 levels were analyzed in T cells.
    RESULTS: Glioblastoma cells show connections between themselves and forms physical connections with T cells through TNTs. Glioblastoma cells hijack mitochondria from T cells through these connections and effect was reversed on using carbenoxolone. Glioblastoma cells show increased mitochondrial membrane potential and decreased mitochondrial ROS after co-culture, while ROS was increased in glioblastoma cells and decreased in T cells.
    CONCLUSION: We show for the first time that glioblastoma cells and T cells physically connect through TNTs. Most importantly, glioblastoma cells hijack the mitochondria of T cells for its own advantage. By focusing on these complex tumor-immune cell interactions, this study aims to uncover a novel mode of physical communication in glioblastoma microenvironment.
    Keywords:  Glioblastoma; Immune cells; Mitochondrial transport; Tumor microenvironment; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/s11060-025-05150-6
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