bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–04–05
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Intercompartmental communication in senescence.
  2. Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice.
  3. Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
  4. Mitochondrial genomes on a string of pearls.
  5. Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells.
  6. Pearling drives mitochondrial DNA nucleoid distribution.
  7. Fluoxetine Acts as a Calcium-Dependent Sensitizer of TRAIL-Induced Apoptosis in Glioblastoma Multiforme.
  8. UCP2 in Glioblastoma Cells Regulates Mitochondrial Metabolic Reprogramming to Mediate Immunophenotypic Repolarization of Tumor-Associated Macrophages and Immunotherapy.
  9. ER-localized ceramide accumulation contributes to replicative senescence.
  10. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  11. Targeting purinergic receptors in glioblastoma with nanobody-displaying AAV vectors.
  1. FEBS Open Bio. 2026 Mar 30.
    Intercompartmental communication in senescence.
    Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.
      Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.
    Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence
    DOI:  https://doi.org/10.1002/2211-5463.70236
  2. EMBO Mol Med. 2026 Apr 01.
    Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice.
    Daniela G Costa, Lucy M Gee, Gung Lee, Lilian Sales Gomez, Ana Catarina Franco, Maria Grazia Vizioli, Karla Valdivieso, Lei J Zhang, Nick Pirius, Helene Martini, Rebecca A Porritt, Dominik Saul, Claudia Cavadas, Scott Ebert, Nathan K LeBrasseur, Sundeep Khosla, João F Passos, Christopher M Adams, Paul D Robbins, Diana Jurk.
      Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identified tomatidine, an aglycone of tomatine found in tomatoes, as a previously unrecognized senotherapeutic agent. In senescent human brain microvascular endothelial cells and fibroblasts, tomatidine selectively suppressed SASP expression without affecting p16Ink4a or p21Cip1 levels consistent with a senomorphic effect. In aged mice, tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by reduced senescence markers (p16 Ink4a, p21 Cip1, and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, along with decreased neuroinflammation and microglial activation. Tomatidine also diminished brain endothelial cell senescence while enhancing tight junction protein expression, suggesting preserved blood-brain barrier integrity. Together, these findings identify tomatidine as a promising senescence-targeting compound with beneficial effects in aged mice and support its further evaluation in mechanistic and translational studies.
    Keywords:  Aging; Brain; Cognition; Senescence; Senomorphic
    DOI:  https://doi.org/10.1038/s44321-026-00400-0
  3. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123
    Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
    Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.
      Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
    Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia
    DOI:  https://doi.org/10.1073/pnas.2508286123
  4. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  5. Aging Dis. 2026 Mar 20.
    Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells.
    Pavel I Deryabin, Aleksandra V Borodkina.
      The accumulation of senescent cells during aging contributes to the progression of various age-related pathologies. Ineffective immune clearance, increased half-life of senescent cells, and bystander senescence are considered the primary drivers of this age-associated accumulation. Most of these causes stem from the aging of the immune system, which results in a prolonged persistence of damaged/nonfunctional cells within tissues and allows the internal senescence program to progress to a more severe phenotype. Here, we propose the existence of an additional immune-independent mechanism underlying the accumulation of senescent cells during aging. By reanalyzing existing experimental evidence, we show that cells of diverse identities and tissue origins become increasingly susceptible to senescence with age. The latter implies that epigenetic and molecular changes that cells acquire during aging create a permissive background for the activation of the senescence program. In light of our findings, senotherapeutic interventions alone may be insufficient to substantially alter the trajectory of organismal aging. Effective strategies may need to target upstream drivers of cellular dysfunction, including age-associated epigenetic alterations. Epigenetic rejuvenation could, in principle, enhance cellular stress resilience and thereby reduce the rate at which senescent cells emerge and accumulate.
    DOI:  https://doi.org/10.14336/AD.2026.0137
  6. Science. 2026 Apr 02. 392(6793): 102-109
    Pearling drives mitochondrial DNA nucleoid distribution.
    Juan C Landoni, Matthew D Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J Obara, Andrew S Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm, Suliana Manley.
      The distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, no known mechanisms can explain nucleoid segregation or their regular positioning. In this work, we found that mitochondria frequently undergo a reversible biophysical instability termed "pearling," transforming from a tubular into a regularly spaced beads morphology. Physiological pearling imposed a characteristic length scale and simultaneously mediated nucleoid disaggregation and established internucleoid distancing with high precision. Pearling onset was triggered by calcium influx, whereas the density of lamellar cristae invaginations modulated pearling prevalence and preserved nucleoid spacing following recovery. The dysregulation of mitochondrial calcium influx or inner membrane cristae integrity caused aberrant nucleoid clustering. Our results identify pearling as a mechanism governing nucleoid distribution and inheritance and offer insights into its regulation.
    DOI:  https://doi.org/10.1126/science.adu5646
  7. ACS Omega. 2026 Mar 24. 11(11): 17796-17809
    Fluoxetine Acts as a Calcium-Dependent Sensitizer of TRAIL-Induced Apoptosis in Glioblastoma Multiforme.
    Shanay H Desai, Nicole S Sarna, Allen C Luo, Michael R King.
      Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with limited therapeutic options and resistance to apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in malignant cells through extrinsic death receptor activation and downstream engagement of the intrinsic mitochondrial pathway, yet its therapeutic efficacy is hindered by intrinsic resistance mechanisms. Here, we demonstrate that the widely used antidepressant fluoxetine (FLX) acts as a potent TRAIL sensitizer by driving Ca2+ influx and mitochondrial priming. In U87MG and LN18 GBM cells, FLX and TRAIL combination therapy significantly reduced cell viability and elicited robust mitochondrial permeabilization compared to monotherapy. Dose-response profiling of TRAIL and FLX revealed strong synergy (Jin's Q-values >2.5) across multiple dose pairs. Mechanistic studies identified GluR1+ AMPA receptor-mediated Ca2+ influx and Bax-dependent mitochondrial permeabilization as central effectors of the combination, while calpain activity served as an enhancer but was not a requirement for apoptosis. Pharmacological inhibition of AMPA receptors or Bax substantially attenuated the apoptotic response, confirming that FLX increased the TRAIL efficacy through Ca2+-mediated amplification of the intrinsic apoptosis pathway. These results identify fluoxetine as a clinically accessible, blood-brain barrier permeable agent that leverages Ca2+ signaling to overcome TRAIL resistance and highlight a novel therapeutic strategy that repurposes SSRIs to potentiate death receptor agonists in GBM.
    DOI:  https://doi.org/10.1021/acsomega.5c12237
  8. J Biochem Mol Toxicol. 2026 Apr;40(4): e70808
    UCP2 in Glioblastoma Cells Regulates Mitochondrial Metabolic Reprogramming to Mediate Immunophenotypic Repolarization of Tumor-Associated Macrophages and Immunotherapy.
    Hailong Du, Xiaoliang Wang, Jianping Sun, Xiaosong Liu, Lei Zhao, Haoming Guo, Jianliang Wu, Jiankai Yang.
      This paper sought to determine whether uncoupling protein 2 (UCP2) regulates the immune phenotype of TAMs by modulating its own mitochondrial metabolic homeostasis in glioblastoma (GBM) cells, thereby influencing anti-tumor treatment response. This study evaluated UCP2 levels in clinical GBM samples and cell lines based on public databases, immunohistochemistry, RT-qPCR, and Western blot. A cell model with specific knockdown of UCP2 was constructed, and cell proliferation, migration and invasion, and apoptosis were detected. ATP measurement, Seahorse analysis, JC-1 staining, H2DCFDA, and MitoSOX staining were employed to assess mitochondrial metabolic function and ROS levels in GBM cells. A GBM-THP-1 co-culture system was established to evaluate the impact of UCP2 knockdown in GBM cells on macrophage polarization. A subcutaneous tumor model was established to evaluate the synergistic effect of UCP2 silencing + anti-PD-L1 therapy. UCP2 was upregulated in GBM tissues and accompanied by increased infiltration of M2-type TAMs. Specific knockdown of UCP2 in GBM cells inhibited cell proliferation and invasion, promoted apoptosis, and induced metabolic reprogramming by inhibiting mitochondrial energy metabolism, reducing mitochondrial membrane potential, and ROS accumulation. Co-culture with GBM cells with UCP2 knockdown promoted macrophage polarization toward the M1 type. UCP2 knockdown + anti-PD-L1 antibody inhibited GBM growth and increased the infiltration of M1-type TAMs. Knockdown of UCP2 in GBM cells reshapes the tumor microenvironment by regulating the tumor cell mitochondrial metabolism, thereby influencing their interaction with TAMs. This promotes M1-type repolarization and enhances the efficacy of anti-tumor treatment, making it a potential therapeutic target.
    Keywords:  UCP2; glioblastoma; metabolic reprogramming; mitochondria; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/jbt.70808
  9. Cell Chem Biol. 2026 Mar 30. pii: S2451-9456(26)00073-5. [Epub ahead of print]
    ER-localized ceramide accumulation contributes to replicative senescence.
    Shweta Chitkara, Mengru Li, Natasha Gozali, Andrey Kuzmin, Artem Pliss, Paras Prasad, Yasemin Sancak, G Ekin Atilla-Gokcumen.
      Ceramides regulate diverse cellular processes through compartment-specific accumulation. While mitochondrial ceramide accumulation promotes apoptosis, its regulation and function during senescence remain incompletely understood. Here, we integrate lipidomics, transcriptomics, Raman spectroscopy, and biochemical characterizations to define sphingolipid remodeling in replicative senescence. Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins, despite unaltered sphingomyelin synthase 1 expression, implicating impaired ceramide-sphingomyelin turnover. Pharmacological inhibition of ceramide transfer protein (CERT), the ER-to-Golgi ceramide transporter, phenocopies sphingolipid remodeling and enhances senescence, suggesting disrupted ceramide trafficking as a driver of senescence. Raman spectroscopy suggests ceramide accumulation localized to the ER. In parallel, analysis of ER-enriched fractions confirms increased ceramide levels in ER fractions of senescent cells. Mechanistically, ceramide accumulation at the ER can contribute to ER stress. These findings identify altered ceramide trafficking as a contributor to ER stress and highlight ER-localized ceramide as a critical component of senescence-associated sphingolipid remodeling.
    Keywords:  ER stress; Raman BCA; ceramide; lipidomics; organelle enrichment; senescence; transcriptomics
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.003
  10. Cell Metab. 2026 Mar 27. pii: S1550-4131(26)00104-X. [Epub ahead of print]
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.010
  11. Neuropharmacology. 2026 Mar 31. pii: S0028-3908(26)00128-0. [Epub ahead of print] 110955
    Targeting purinergic receptors in glioblastoma with nanobody-displaying AAV vectors.
    Saruul Jargalsaikhan, Waldemar Schäfer, Niclas Zapf, Merle Reetz, Daniel García Rodríguez, Paolo Malatesta, Peter Bannas, Lasse Dührsen, Malte Mohme, Katrin Lamszus, Friedrich Koch-Nolte, Cecile L Maire, Anna Marei Mann.
      The standard therapy for glioblastoma, surgery followed by radio- and chemotherapy, results in ATP release from damaged and stressed cells. The GPI-anchored ecto-enzyme CD73 and the ATP-gated P2X7 ion channel are often expressed on glioblastoma cells. CD73 contributes to the cold tumor microenvironment by generating immunosuppressive adenosine. P2X7 promotes tumor growth by enhancing cell proliferation and survival. Here we show that these membrane proteins can serve as entry receptors for recombinant Adeno-associated viruses (AAV). To this end, we genetically inserted CD73-specific or P2X7-specific nanobodies into a surface loop of the AAV9 capsid. These nanobody-displaying AAV greatly enhanced the transduction of CD73- or P2X7-expressing HEK cells in vitro and patient-derived glioblastoma cells ex vivo. Our results pave the way for the therapeutic application of these nanobody-displaying AAV, for example, to express immune-activating cytokines or checkpoint inhibitors in the tumor cells to turn a cold tumor microenvironment hot.
    Keywords:  Adeno-associated virus; glioblastoma; ligand-insertion; nanobody; purinergic; single-domain antibody; targeted AAV
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110955
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