bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–02–16
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Berberine is a Novel Mitochondrial Calcium Uniporter Inhibitor that Disrupts MCU-EMRE Assembly.
  2. Pyruvate Carboxylase as a Moonlighting Metabolic Enzyme Protects β-Cell From Senescence.
  3. The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.
  4. Functional investigation of a putative calcium-binding site involved in the inhibition of inositol 1,4,5-trisphosphate receptor activity.
  5. Senescence as a Molecular Target in Skin Aging and Disease.
  6. Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
  7. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.
  8. Transcriptional activation of genes associated with the matrisome is a common feature of senescent endothelial cells.
  9. Mitochondrial succinate feeds T cell exhaustion in cancer.
  10. The promise of mitochondria in the treatment of glioblastoma: a brief review.
  11. ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
  12. Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.
  13. Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.
  14. Etoposide-induced cancer cell death: roles of mitochondrial VDAC1 and calpain, and resistance mechanisms.
  1. Adv Sci (Weinh). 2025 Feb 07. e2412311
    Berberine is a Novel Mitochondrial Calcium Uniporter Inhibitor that Disrupts MCU-EMRE Assembly.
    Haixin Zhao, Siqi Chen, Nian Cao, Wenjun Wu, Guangqin Liu, Jun Gao, Jiayi Chen, Ting Li, Dingyi Lu, Lingmin Zeng, Haizhen Zhu, Weina Zhang, Qing Xia, Teng Li, Tao Zhou, Xue-Min Zhang, Ai-Ling Li, Xin Pan.
      The mitochondrial calcium uniporter (MCU) complex mediates Ca2+ entry into mitochondria, which plays a crucial role in regulating cellular energy metabolism and apoptosis. Dysregulation of MCU is implicated in various diseases, such as neurodegenerative disorders, cardiac diseases, and cancer. Despite its importance, developing specific and clinically viable MCU inhibitors is challenging. Here, Berberine, a well-established drug with a documented safety profile, is identified as a potent MCU inhibitor through a virtual screening of an FDA-approved drug library. Berberine localizes within mitochondria and directly binds to the juxtamembrane loop domain of MCU. This binding disrupts the interaction of MCU with its essential regulator, EMRE, thereby inhibiting rapid Ca2+ entry into the mitochondria. Notably, Berberine pretreatment reduces mitochondrial Ca2+ overload and mitigates ischemia/reperfusion-induced myocardial injury in mice. These findings establish Berberine as a potent MCU inhibitor, offering a safe therapeutic strategy for diseases associated with dysregulated mitochondrial calcium homeostasis.
    Keywords:  EMRE; MCU (mitochondrial calcium uniporter); berberine; mitochondrial calcium signaling; myocardial injury; small molecules
    DOI:  https://doi.org/10.1002/advs.202412311
  2. J Diabetes. 2025 Feb;17(2): e70050
    Pyruvate Carboxylase as a Moonlighting Metabolic Enzyme Protects β-Cell From Senescence.
    Yumei Yang, Baomin Wang, Xiaomu Li.
      
    Keywords:  diabetes; pyruvate carboxylase; senescence
    DOI:  https://doi.org/10.1111/1753-0407.70050
  3. Open Biol. 2025 Feb;15(2): 240287
    The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.
    Richard M Monaghan.
      This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.
    Keywords:  ageing; endoplasmic reticulum; healthspan; membrane contact sites; metabolism; mitochondria
    DOI:  https://doi.org/10.1098/rsob.240287
  4. J Biol Chem. 2025 Feb 11. pii: S0021-9258(25)00150-4. [Epub ahead of print] 108302
    Functional investigation of a putative calcium-binding site involved in the inhibition of inositol 1,4,5-trisphosphate receptor activity.
    Vikas Arige, Larry E Wagner, Sundeep Malik, Mariah R Baker, Guizhen Fan, Irina I Serysheva, David I Yule.
      The regulation of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) activity is thought to define the spatiotemporal patterns of Ca2+ signals necessary for the appropriate activation of downstream effectors. The binding of both IP3 and Ca2+ are obligatory for IP3R channel opening. Ca2+, however regulates IP3R activity in a biphasic manner. Ca2+ binding to a high-affinity pocket formed by the ARM3 domain and linker domain promotes IP3R channel opening without altering the Ca2+ dependency for channel inactivation. These data suggest a distinct low-affinity Ca2+ binding site is responsible for the reduction in IP3R activity at higher [Ca2+]. We mutated a cluster of acidic residues in the ARM2 and central linker domain of IP3R type-1, reported to coordinate Ca2+ in cryo-EM structures of the IP3R type 3. This "CD Ca2+ binding site" is well-conserved in all IP3R sub-types. CD site Ca2+ binding mutants where the negatively charged glutamic acid residues were mutated to alanine exhibited enhanced sensitivity to IP3-generating agonists. Ca2+ binding mutants displayed spontaneous elemental Ca2+ puffs and the number of IP3-induced Ca2+ puffs were augmented in cells stably expressing Ca2+ binding site mutants. The inhibitory effect of high [Ca2+] on single channel-open probability (Po) was reduced in mutant channels and this effect was dependent on [ATP]. This indicates that Ca2+ binding to the putative CD Ca2+ inhibitory site facilitates the reduction in IP3R channel activation at subsaturating, likely physiological cytosolic [ATP], and suggest that at higher [ATP], additional Ca2+ binding motifs may contribute to the biphasic regulation of IP3-induced Ca2+ release.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108302
  5. Ageing Res Rev. 2025 Feb 08. pii: S1568-1637(25)00032-7. [Epub ahead of print] 102686
    Senescence as a Molecular Target in Skin Aging and Disease.
    Henriette Thau, Bastian P Gerjol, Katharina Hahn, Rosalie Wolff von Gudenberg, Leonard Knoedler, Kenneth Stallcup, Maximilian Y Emmert, Timo Buhl, Saranya P Wyles, Tamar Tchkonia, Stefan G Tullius, Jasper Iske.
      Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key driver of physiological and pathological skin aging. Increasing evidence points towards the role of senescence in a variety of dermatological diseases, where the accumulation of senescent cells in the epidermis and dermis exacerbates disease progression. Emerging therapeutic strategies such as senolytics and senomorphics offer promising avenues to target senescent cells and mitigate their deleterious effects, providing potential treatments for both skin aging and senescence-associated skin diseases. This review explores the molecular mechanisms of cellular senescence and its role in promoting age-related skin changes and pathologies, while compiling the observed effects of senotherapeutics in the skin and discussing the translational relevance.
    Keywords:  Skin aging; anti-aging; senescence; senescent cell, senolytics
    DOI:  https://doi.org/10.1016/j.arr.2025.102686
  6. Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968
    Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
    Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.
      Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.
    Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
  7. Elife. 2025 Feb 14. pii: RP99971. [Epub ahead of print]13
    fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.
    Angela M Tuckowski, Safa Beydoun, Elizabeth S Kitto, Ajay Bhat, Marshall B Howington, Aditya Sridhar, Mira Bhandari, Kelly Chambers, Scott F Leiser.
      Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.
    Keywords:  C. elegans; ER; aging; calcium; flavin-containing monooxygenase; genetics; genomics; mitochondria; stress resistance
    DOI:  https://doi.org/10.7554/eLife.99971
  8. Biogerontology. 2025 Feb 13. 26(2): 59
    Transcriptional activation of genes associated with the matrisome is a common feature of senescent endothelial cells.
    Ignacia González, Sebastián B Arredondo, Rodrigo Maldonado-Agurto.
      Cellular senescence is a stable cell cycle arrest that occurs in response to various stress stimuli and affects multiple cell types, including endothelial cells (ECs). Senescent cells accumulate with age, and their removal has been linked to reduced age-related diseases. However, some senescent cells are important for tissue homeostasis. Therefore, understanding the diversity of senescent cells in a cell-type-specific manner and their underlying molecular mechanisms is essential. Senescence impairs key ECs functions which are necessary for vascular homeostasis, leading to endothelial dysfunction and age-related vascular diseases. In order to gain insights into these mechanisms, we analyzed publicly available RNA-seq datasets to identify gene expression changes in senescent ECs induced by doxorubicin, irradiation, and replication exhaustion. While only a few genes were consistently differentially expressed across all conditions, some gene ontologies (GO) were shared. Among these, our analysis focused on validating the expression of genes associated with the matrisome, which includes genes encoding for extracellular matrix (ECM) structural components and ECM-associated proteins, in a doxorubicin-induced senescence model. Our results show that the matrisome transcriptome undergoes significant remodeling in senescent endothelial cells, regardless of the specific inducers of senescence, highlighting the importance of understanding how ECM alterations affect senescence.
    Keywords:  Cellular senescence; Endothelial cells; Extracellular matrix; Matrisome; RNA-seq
    DOI:  https://doi.org/10.1007/s10522-025-10191-5
  9. Cancer Cell. 2025 Feb 10. pii: S1535-6108(25)00023-6. [Epub ahead of print]43(2): 168-170
    Mitochondrial succinate feeds T cell exhaustion in cancer.
    Lorenzo Galluzzi, Emma Guilbaud, Abhishek D Garg.
      Mitochondrial fitness is critical for effector CD8+ T cell responses against cancer. In this issue of Cancer Cell, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2025.01.005
  10. Discov Oncol. 2025 Feb 09. 16(1): 142
    The promise of mitochondria in the treatment of glioblastoma: a brief review.
    Zhuo Liang, Songyun Zhao, Yuankun Liu, Chao Cheng.
      Glioblastoma (GBM) is a prevalent and refractory type of brain tumor. Over the past two decades, there have been minimal advancements in GBM therapy. The current standard treatment involves surgical excision followed by radiation and chemotherapy. Compared to other tumors, GBM is more challenging to treat due to the presence of glioma stem-like cells (GSCs) and the blood-brain barrier, resulting in an extremely low survival rate. Mitochondria play a critical role in tumor respiration, metabolism, and multiple signaling pathways involved in tumor formation, progression, and cell apoptosis. Consequently, mitochondria represent promising targets for developing novel anticancer agents, including those targeting oxidative phosphorylation, reactive oxygen species (ROS), mitochondrial transfer, and mitophagy. This review outlines the mitochondrial-related therapeutic targets in GBM, highlighting the potential of mitochondria as a target for GBM treatment.
    Keywords:  Glioblastoma; Mitochondria; Mitochondrial autophagy; Mitochondrial metastasis; Oxidative phosphorylation; ROS
    DOI:  https://doi.org/10.1007/s12672-025-01891-y
  11. Nat Commun. 2025 Feb 10. 16(1): 1508
    ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
    Isshin Shiiba, Naoki Ito, Hijiri Oshio, Yuto Ishikawa, Takahiro Nagao, Hiroki Shimura, Kyu-Wan Oh, Eiki Takasaki, Fuya Yamaguchi, Ryoan Konagaya, Hisae Kadowaki, Hideki Nishitoh, Takehito Tanzawa, Shun Nagashima, Ayumu Sugiura, Yuuta Fujikawa, Keitaro Umezawa, Yasushi Tamura, Byung Il Lee, Yusuke Hirabayashi, Yasushi Okazaki, Tomohiro Sawa, Ryoko Inatome, Shigeru Yanagi.
      The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-025-56666-4
  12. FEBS J. 2025 Feb 11.
    Intercellular mitochondrial transfer contributes to microenvironmental redirection of cancer cell fate.
    Julie Sofie Bjerring, Yara Khodour, Emilee Anne Peterson, Patrick Christian Sachs, Robert David Bruno.
      The mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) by which this alteration occurs has yet to be defined. Here, we test the hypothesis that mitochondrial transfer from normal mammary epithelial cells to breast cancer cells plays a role in this redirection process. We evaluate mitochondrial transfer in 2D and 3D organoids using our unique 3D bioprinting system to produce chimeric organoids containing normal and cancer cells. We demonstrate that breast cancer tumoroid growth is hindered following interaction with mammary epithelial cells in both 2D and 3D environments. Furthermore, we show mitochondrial transfer occurs between donor mammary epithelial cells and recipient cancer cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria, likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, reducing their proliferative potential, and making them susceptible to microenvironmental control. Our results demonstrate that mitochondrial transfer contributes to microenvironmental redirection of cancer cells through alteration of metabolic and molecular functions of the recipient cancer cells. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection of cancer and provide a framework for new therapeutic strategies to control cancer.
    Keywords:  3D bioprinting; breast cancer; cellular redirection; microenvironment; mitochondrial transfer
    DOI:  https://doi.org/10.1111/febs.70002
  13. Cell Mol Life Sci. 2025 Feb 08. 82(1): 73
    Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.
    Maria Rosito, Javeria Maqbool, Alice Reccagni, Micol Mangano, Tiziano D'Andrea, Arianna Rinaldi, Giovanna Peruzzi, Beatrice Silvestri, Alessandro Rosa, Flavia Trettel, Giuseppina D'Alessandro, Myriam Catalano, Sergio Fucile, Cristina Limatola.
      The use of a ketogenic diet (KD) in glioma is currently tested as an adjuvant treatment in standard chemotherapy regimens. The metabolic shift induced by the KD leads to the generation of ketone bodies that can influence glioma cells and the surrounding microenvironment, but the mechanisms have not yet been fully elucidated. Here, we investigated the potential involvement of glial cells as mediators of the KD-induced effects on tumor growth and survival rate in glioma-bearing mice. Specifically, we describe that exposing glioma-bearing mice to a KD or to β-hydroxybutyrate (β-HB), one of the main KD metabolic products, reduced glioma growth in vivo, induced a pro-inflammatory phenotype in astrocytes and increased functional glutamate transporters. Moreover, we described increased intracellular basal Ca2+ levels in GL261 glioma cells treated with β-HB or co-cultured with astrocytes. These data suggest that pro-inflammatory astrocytes triggered by β-HB can be beneficial in counteracting glioma proliferation and neuronal excitotoxicity, thus protecting brain parenchyma.
    Keywords:  Astrocytes; Astrogliosis; Glioma; Ketogenic diet; Microglia; Pro-inflammatory astrocytes; β-HB
    DOI:  https://doi.org/10.1007/s00018-025-05600-4
  14. Mol Oncol. 2025 Feb 07.
    Etoposide-induced cancer cell death: roles of mitochondrial VDAC1 and calpain, and resistance mechanisms.
    Aditya Karunanithi Nivedita, Varda Shoshan-Barmatz.
      Etoposide is an inhibitor of DNA topoisomerase II, an enzyme essential for DNA transcription, replication, and chromosome segregation. It is well accepted that etoposide triggers cell death due to DNA damage. Our results indicate that multiple molecular mechanisms contribute to etoposide-induced apoptosis, including the overexpression of the mitochondrial voltage-dependent anion channel 1 (VDAC1) and its oligomerization, forming a mega-channel that releases pro-apoptotic proteins, thereby activating apoptosis. Etoposide induces C-terminal truncation of VDAC1 (VDAC1-ΔC) via the proteolytic actions of calpain-1 and asparagine endopeptidase (AEP). A calpain-specific inhibitor effectively prevented etoposide-induced VDAC1-ΔC formation, apoptosis, and the nuclear translocation of apoptosis-inducing factor (AIF). Additionally, etoposide upregulates the expression levels of apoptosis regulators (p53, Bax, p21, AIF) and of the proteases calpain and AEP. Etoposide-induced apoptosis and VDAC1 truncation are cell-type dependent and associated with calpain levels and activity. Etoposide-induced VDAC1-ΔC formation and apoptosis are tightly linked: as both display similar patterns of concentration- and time-dependence, both are inhibited by calpain and AEP inhibitors, as well as the VDAC1 oligomerization inhibitor VBIT-4, and are dependent on intracellular Ca2+. These findings highlight the complexity of etoposide's actions in different cellular contexts, suggest possible mechanisms of resistance, offer potential biomarkers for guiding etoposide treatment in cancer patients, and propose targeting VDAC1 and calpain as promising therapeutic strategies in cancer therapy.
    Keywords:  VDAC1; apoptosis; calpain; etoposide; mitochondria; topoisomerase inhibitors
    DOI:  https://doi.org/10.1002/1878-0261.13807
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒16 at 14:39.