bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–03–23
thirteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  2. Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP).
  3. Optogenetic tools for inducing organelle membrane rupture.
  4. SIRT5 slows skeletal muscle ageing by alleviating inflammation.
  5. How extreme lethargy can promote healthy ageing.
  6. Comparative Analysis of SPLICS and MCS-DETECT for Detecting Mitochondria-ER Contact Sites (MERCs).
  7. Developmental mitochondrial complex I activity determines lifespan.
  8. SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1.
  9. Nicotinamide metabolism reprogramming drives reversible senescence of glioblastoma cells.
  10. Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.
  11. Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice.
  12. Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
  13. A dual-enzyme activated fluorescent probe for precise identification of tumor senescence.
  1. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  2. Aging (Albany NY). 2025 Mar 20. null
    Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP).
    Sudipta Bar, Tyler A U Hilsabeck, Blaine Pattavina, José Alberto López-Domínguez, Nathan Basisty, Joanna Bons, Mark Watson, Birgit Schilling, Judith Campisi, Pankaj Kapahi, Amit Sharma.
      Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.
    Keywords:  SASP; aging; drosophila; senescence
    DOI:  https://doi.org/10.18632/aging.206224
  3. J Biol Chem. 2025 Mar 18. pii: S0021-9258(25)00270-4. [Epub ahead of print] 108421
    Optogenetic tools for inducing organelle membrane rupture.
    Yuto Nagashima, Tomoya Eguchi, Ikuko Koyama-Honda, Noboru Mizushima.
      Disintegration of organelle membranes induces various cellular responses and has pathological consequences, including autoinflammatory diseases and neurodegeneration. Establishing methods to induce membrane rupture of specific organelles is essential to analyze the downstream effects of membrane rupture; however, the spatiotemporal induction of organelle membrane rupture remains challenging. Here, we develop a series of optogenetic tools to induce organelle membrane rupture by using engineered Bcl-2-associated X protein (BAX), which primarily functions to form membrane pores in the outer mitochondrial membrane (OMM) during apoptosis. When BAX is forced to target mitochondria, lysosomes, or the endoplasmic reticulum (ER) by replacing its C-terminal transmembrane domain (TMD) with organelle-targeting sequences, the BAX mutants rupture their targeted membranes. To regulate the activity of organelle-targeted BAX, the photosensitive light-oxygen-voltage-sensing 2 (LOV2) domain is fused to the N-terminus of BAX. The resulting LOV2-BAX fusion protein exhibits blue light-dependent membrane-rupture activity on various organelles, including mitochondria, the ER, and lysosomes. Thus, LOV2-BAX enables spatiotemporal induction of membrane rupture across a broad range of organelles, expanding research opportunities on the consequences of organelle membrane disruption.
    Keywords:  Bcl-2-associated X protein (BAX); Membrane rupture; light-oxygen-voltage-sensing 2 (LOV2) domain; lysosomal membrane permeabilization (LMP); mitochondrial outer membrane permeabilization (MOMP); optogenetics
    DOI:  https://doi.org/10.1016/j.jbc.2025.108421
  4. Nat Metab. 2025 Mar 14.
    SIRT5 slows skeletal muscle ageing by alleviating inflammation.
    Vera Gorbunova, Andrei Seluanov.
      
    DOI:  https://doi.org/10.1038/s42255-025-01228-7
  5. Nature. 2025 Mar;639(8055): 549
    How extreme lethargy can promote healthy ageing.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00707-x
  6. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251313721
    Comparative Analysis of SPLICS and MCS-DETECT for Detecting Mitochondria-ER Contact Sites (MERCs).
    Jieyi Zheng, Ben Cardoen, Milene Ortiz-Silva, Ghassan Hamarneh, Ivan R Nabi.
      Detection of mitochondria-ER contacts (MERCs) from diffraction limited confocal images commonly uses fluorescence colocalization analysis of mitochondria and endoplasmic reticulum (ER) as well as split fluorescent probes, such as the split-GFP-based contact site sensor (SPLICS). However, inter-organelle distances (∼10-60 nm) for MERCs are lower than the 200-250 nm diffraction limited resolution obtained by standard confocal microscopy. Super-resolution microscopy of 3D volume analysis provides a two-fold resolution improvement (∼120 nm XY; 250 nm Z), which remains unable to resolve MERCs. MCS-DETECT, a membrane contact site (MCS) detection algorithm faithfully detects elongated ribosome-studded riboMERCs when applied to 3D STED super-resolution image volumes. Here, we expressed the SPLICSL reporter in HeLa cells co-transfected with the ER reporter RFP-KDEL and label fixed cells with antibodies to RFP and the mitochondrial protein TOM20. MCS-DETECT analysis of 3D STED volumes was compared to contacts determined by co-occurrence colocalization analysis of mitochondria and ER or the SPLICSL probe. Percent mitochondria coverage by MCS-DETECT derived contacts was significantly smaller than those obtained for colocalization analysis or SPLICSL, and more closely matched contact site metrics obtained by 3D electron microscopy. Further, STED analysis localized a subset of the SPLICSL label to mitochondria with some SPLICSL puncta observed to be completely enveloped by mitochondria in 3D views. These data suggest that MCS-DETECT reports on a limited set of MERCs that more closely corresponds to those observed by EM.
    Keywords:  MCS-DETECT; SPLICS; mitochondria-ER contact sites; stimulated emission depletion microscopy; super-resolution microscopy
    DOI:  https://doi.org/10.1177/25152564251313721
  7. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  8. Nat Metab. 2025 Mar 14.
    SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1.
    Qian Zhao, Ying Jing, Xiaoyu Jiang, Xin Zhang, Feifei Liu, Haoyan Huang, Zhihua Zhang, Haijun Wang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Xiaobing Fu, Guoguang Zhao, Jing Qu, Si Wang, Guang-Hui Liu.
      Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5-TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration.
    DOI:  https://doi.org/10.1038/s42255-025-01235-8
  9. Cell Mol Life Sci. 2025 Mar 21. 82(1): 126
    Nicotinamide metabolism reprogramming drives reversible senescence of glioblastoma cells.
    Ashwin Narayanan, Mirca S Saurty-Seerunghen, Jessica Michieletto, Virgile Delaunay, Arnaud Bruneel, Thierry Dupré, Chris Ottolenghi, Clément Pontoizeau, Lucrezia Ciccone, Andreas De La Vara, Ahmed Idbaih, Laurent Turchi, Thierry Virolle, Hervé Chneiweiss, Marie-Pierre Junier, Elias A El-Habr.
      Recent studies show that metabolites, beyond their metabolic roles, can induce significant changes in cell behavior. Herein, we investigate the non-canonical role of nicotinamide (vitamin B3) on glioblastoma (GB) cell behavior. Nicotinamide induced senescence in GB cells, characterized by reduced proliferation, chromatin reorganization, increased DNA damage, enhanced beta-galactosidase activity, and decreased Lamin B1 expression. Nicotinamide-induced senescence was accompanied by an unexpected reprogramming of its metabolism, marked by simultaneous downregulated transcription of NNMT (nicotinamide N-methyltransferase) and NAMPT (nicotinamide phosphoribosyl-transferase). Nicotinamide effects on GB cells were mediated by decreased levels of SOX2. Consistently, analyses of patients' single cell transcriptome datasets showed that GB cells with low NNMT and NAMPT expression levels were enriched in gene modules related to senescence. Remarkably, senescent GB cells retained tumor-forming ability in vivo, albeit to a lesser extent compared to control cells. Further experiments at the single-cell level and transcriptomic analyses demonstrated that nicotinamide-induced senescence in GB cells is fully reversible. Overall, our findings identify a novel reversible senescent state in GB tumors and highlight the non-canonical role of nicotinamide as a key driver of cancer cell plasticity.
    Keywords:  CD44; H3K14ac; H3K27me3; Sc-RNAseq
    DOI:  https://doi.org/10.1007/s00018-025-05641-9
  10. Am J Physiol Cell Physiol. 2025 Mar 19.
    Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.
    Joachim Nielsen, Kristine Grøsfjeld Petersen, Martin Eisemann de Almeida, Sam O Shepherd, Britt Christensen, Maria Houborg Petersen, Kurt Højlund, Niels Ørtenblad, Kasper Degn Gejl.
      Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles' size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria total contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria (+30%) and LDs (+100%) in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater total LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (r=0.72) with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibers rich in mitochondria.
    Keywords:  PLIN5; endurance performance; fat oxidation; lipid droplets; metabolism; mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00123.2025
  11. Sci Adv. 2025 Mar 21. 11(12): eadr1378
    Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice.
    Cristina Mas-Bargues, Aurora Román-Domínguez, Jorge Sanz-Ros, Nekane Romero-García, Javier Huete-Acevedo, Mar Dromant, Ana María Cuervo, Consuelo Borrás, José Viña.
      Our previous transcriptomic analysis revealed an up-regulation of the antiapoptotic protein B cell lymphoma-extra large (Bcl-xL) in centenarians relative to octogenarians or younger cohorts. In this study, we used Bcl-xL-overexpressing mice to assess its impact on successful aging. Our findings indicate that Bcl-xL overexpression modifies T cell subsets and improves their metabolism, apoptosis resistance, macroautophagy, and cytokine production during aging. This more resilient immune system reduces inflammation and preserves mitochondrial integrity and function in muscle tissue, thereby retarding the onset of frailty. These results underscore the important contribution of Bcl-xL to healthy aging, a phenomenon that is conserved across mammalian species.
    DOI:  https://doi.org/10.1126/sciadv.adr1378
  12. Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00081-9. [Epub ahead of print]
    Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
    Michael V Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A Rushworth, Jiri Neuzil.
      Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.002
  13. Chem Sci. 2025 Mar 11.
    A dual-enzyme activated fluorescent probe for precise identification of tumor senescence.
    Xianzhu Luo, Erzhuo Hu, Fei Deng, Cuiling Zhang, Yuezhong Xian.
      Precise recognition of senescent cells is essential owing to their key role in various diseases, including aging and tumor suppression. Although senescence-associated β-galactosidase (SA-β-Gal) is widely used as a senescence biomarker, it is not remarkably accurate due to its overexpression in some non-senescent cells. Herein, we developed a dual-channel fluorescent probe to improve the identification accuracy of senescent cells through simultaneous detection of β-gal and α-l-fucosidase (AFU) because the two markers are upregulated in senescent cells. The dual-channel fluorescent probe named HDQ-NA-AFU-Gal was employed to detect β-gal and AFU and identify senescence in living cells and tumor-bearing mice. When the two are present, the dual-enzyme activated probe emits strong red and green fluorescence at 740 nm and 550 nm, respectively, enabling independent detection of β-gal and AFU. This dual-enzyme detection approach allows for the precise differentiation between normal and senescent cells, particularly in ovarian cancer cells overexpressing β-gal. Furthermore, the probe can be applied as an effective tool for tracing β-gal and AFU during tumor senescence in mice. Thus, the dual-enzyme-responsive fluorescent probe has promising applications in biological research and clinical medicine.
    DOI:  https://doi.org/10.1039/d5sc00103j
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