bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–12–07
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. CCK-elicited pancreatic Ca2+ signalling and function likely requires IP3 formation.
  2. The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a HIF2A-Dependent Upregulation and a FURIN-Dependent Cleavage of the ANGPTL4 Secreted Factor.
  3. Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
  4. Nociceptin-mediated SIRT6 downregulation drives cellular senescence in glioblastoma.
  5. Lactobacillus johnsonii JNU3402 Ameliorates Age-Related Liver Dysfunction Through Stimulating PGC-1α-Mediated SIRT1 Expression.
  6. Endoplasmic reticulum, mitochondria, and their crosstalk in retinal ganglion cell degeneration.
  7. Protein restriction reshapes aging across organs.
  8. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
  9. Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
  10. The differences in molecular profiles and survival outcomes between early-onset and late-onset glioblastoma multiforme.
  11. Mitochondrial Metabolic Reprogramming along with NRF2/KEAP1-Mediated Antioxidant Mechanisms Drive Temozolomide Resistance in Glioblastoma Multiforme.
  12. Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
  1. J Physiol. 2025 Nov 30.
    CCK-elicited pancreatic Ca2+ signalling and function likely requires IP3 formation.
    David I Yule.
      
    Keywords:  Ca2+ signalling; Inositol 1,4,5‐trisphosphate; NAADP; acetylcholine; cholecystokinin; pancreatic acinar cells
    DOI:  https://doi.org/10.1113/JP290490
  2. Aging Cell. 2025 Dec 05. e70307
    The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a HIF2A-Dependent Upregulation and a FURIN-Dependent Cleavage of the ANGPTL4 Secreted Factor.
    Gabriela Makulyte, Hasan Safwan-Zaiter, Delphine Goehrig, Anda Huna, Adèle Mangelinck, Takumi Mikawa, Alberta Palazzo, Lyvia Moudombi, Jean-Jacques Medard, Marie Chanal, Pacôme Lecot, Marie-Cécile Michallet, Julie Gavard, Serge Adnot, Pierre Dubus, Hiroshi Kondoh, Carl Mann, Nguan Soon Tan, Philippe Bertolino, Jean-Michel Flaman, David Bernard.
      Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases.
    Keywords:  ANGPTL4; age‐related diseases; cancer; cellular senescence; inflammation; senescence‐associated secretory phenotype
    DOI:  https://doi.org/10.1111/acel.70307
  3. Nat Metab. 2025 Dec 03.
    Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
    Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.
    DOI:  https://doi.org/10.1038/s42255-025-01412-9
  4. Neuropeptides. 2025 Nov 27. pii: S0143-4179(25)00070-8. [Epub ahead of print]115 102570
    Nociceptin-mediated SIRT6 downregulation drives cellular senescence in glioblastoma.
    Yankai Xu, Jiesi Zhou, Xiaobin Zhou, Yong Li, Senyuan Yang, Zebin Xue.
      Cellular senescence plays a crucial role in glioblastoma (GBM), influencing tumor progression and therapeutic resistance. Nociceptin (N/OFQ), an endogenous neuropeptide, and its receptor NOPr are implicated in various pathological processes, but their role in GBM remains unclear. This study investigated the effects of N/OFQ-NOPr signaling on cellular senescence in GBM. We found elevated plasma N/OFQ levels and increased NOPr expression in GBM tissues compared to normal controls. In U-251 GBM cells, N/OFQ upregulated NOPr expression, induced oxidative stress, and reduced telomerase activity and telomere length, leading to enhanced cellular senescence. Mechanistically, N/OFQ downregulated SIRT6 but not SIRT1 or HDAC, resulting in increased acetylation of p53, upregulation of p21, and suppression of p-Rb. Overexpression of SIRT6 reversed N/OFQ-induced senescence markers, restoring telomerase activity and reducing senescence-associated β-galactosidase. Notably, administration of the selective NOPr antagonist UFP-101 abolished N/OFQ-induced cellular senescence, indicating that this effect is NOPr-dependent. These findings suggest that N/OFQ-NOPr signaling promotes GBM senescence via SIRT6 downregulation, highlighting a potential therapeutic target for modulating senescence in GBM.
    Keywords:  Glioblastoma; Nociceptin; SIRT6; Senescence; p53
    DOI:  https://doi.org/10.1016/j.npep.2025.102570
  5. Biofactors. 2025 Nov-Dec;51(6):51(6): e70069
    Lactobacillus johnsonii JNU3402 Ameliorates Age-Related Liver Dysfunction Through Stimulating PGC-1α-Mediated SIRT1 Expression.
    Eunjeong Hong, Garam Yang, Sejong Oh, Eungseok Kim.
      Lactobacillus johnsonii JNU3402 (LJ3402) has previously been reported to ameliorate diet-induced hepatic steatosis. Because aging is tightly linked to metabolic disease, we hypothesized that LJ3402 might protect against age-related metabolic abnormalities in the liver. This study presents data demonstrating that LJ3402 administration reduces hepatic dysfunction in 24-month-old mice alongside the alleviation of general aging phenotypes. Furthermore, LJ3402 increased hepatic expression of genes involved in mitochondrial function and decreased senescence markers, thereby limiting age-related mitochondrial dysfunction and hepatocyte senescence, contributing to the attenuation of metabolic dysfunction-associated steatotic liver disease (MASLD) progression. Mechanistically, LJ3402 enhanced sirtuin 1 (SIRT1) expression in AML12 hepatocytes by stimulating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) coactivation of peroxisome proliferator-activated receptor alpha (PPARα). Consequently, SIRT1 suppressed p53 acetylation and activity in senescent AML12 cells, reducing senescence markers and mitochondrial dysfunction. Thus, LJ3402 suppresses mitochondrial dysfunction and senescence of hepatocytes by stimulating the PGC-1α-SIRT1-p53 pathway, reducing age-related hepatic lipid accumulation.
    Keywords:  Lactobacillus johnsonii JNU3402; aging; metabolic dysfunction‐associated steatotic liver disease; mitochondrial function; senescence
    DOI:  https://doi.org/10.1002/biof.70069
  6. Biomed Pharmacother. 2025 Nov 29. pii: S0753-3322(25)01029-7. [Epub ahead of print]193 118835
    Endoplasmic reticulum, mitochondria, and their crosstalk in retinal ganglion cell degeneration.
    Baohua Li, Yipeng Shi, Mengyu Liu, Wengxuan Cao, Fuyuan Zhang, Zefeng Kang.
      Retinal ganglion cells (RGCs) serve as the terminal output neurons in the retina and are responsible for transmitting visual information from photoreceptors to higher-level centers in the brain. Because of their highly polarized structure, substantial energy demands, and complex protein synthesis activities, the function of RGCs is critically dependent on the homeostasis of intracellular organelles, particularly the endoplasmic reticulum (ER) and mitochondria. Recent studies have shown that these two organelles engage in close physical and functional crosstalk through specific microdomains known as "mitochondria-associated ER membranes" (MAMs), which are crucial for the survival and function of RGCs. This review delves into the critical roles of the ER and mitochondria in the mechanisms of RGC degeneration. Furthermore, the mechanisms by which mitochondrial-ER contact site (MERC)-mediated interorganelle communication exacerbates RGC degeneration by disrupting Ca2 + homeostasis and inducing ER stress and oxidative stress are elucidated. Drugs targeting mitochondria, ER, and MERCs to prevent and treat RGC degeneration are summarized to provide new perspectives and references for studying the pathological mechanisms of RGC degeneration and developing targeted therapeutic strategies.
    Keywords:  Endoplasmic reticulum; Mitochondria; Mitochondria-associated membrane; Retinal ganglion cell; Retinal neuron degeneration
    DOI:  https://doi.org/10.1016/j.biopha.2025.118835
  7. Nat Aging. 2025 Dec 03.
    Protein restriction reshapes aging across organs.
    Qingzhong Ren.
      
    DOI:  https://doi.org/10.1038/s43587-025-01043-5
  8. Cell Metab. 2025 Dec 03. pii: S1550-4131(25)00486-3. [Epub ahead of print]
    Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
    Yan Huang, Biao Hu, Ya Liu, Ling-Qi Xie, Yu Dai, Yu-Ze An, Xin-Yi Peng, Ya-Lun Cheng, Yi-Fan Guo, Wei-Hong Kuang, Yao Xiao, Xin Chen, Yong-Jun Zheng, Gen-Qing Xie, Jian-Ping Wang, Hui Peng, Xiang-Hang Luo.
      Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.
    Keywords:  MDVs; cognitive decline; excessive vigorous exercise
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.002
  9. Nat Metab. 2025 Dec 03.
    Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
    Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves.
      Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
    DOI:  https://doi.org/10.1038/s42255-025-01411-w
  10. Genes Dis. 2026 Mar;13(2): 101638
    The differences in molecular profiles and survival outcomes between early-onset and late-onset glioblastoma multiforme.
    Yukui Wei, Xiaolong Wu, Hua Bao, Yao Xiao, Huantong Diao, Siheng Liu, Bingyang Shan, Peng Ding, Ye Cheng, Xinru Xiao.
      
    DOI:  https://doi.org/10.1016/j.gendis.2025.101638
  11. J Proteome Res. 2025 Dec 05.
    Mitochondrial Metabolic Reprogramming along with NRF2/KEAP1-Mediated Antioxidant Mechanisms Drive Temozolomide Resistance in Glioblastoma Multiforme.
    Manendra Singh Tomar, Chirag Kulkarni, Kaveri R Washimkar, Shobhit Verma, Amita Bhadkaria, Fabrizio Araniti, Madhav Nilakanth Mugale, Naibedya Chattopadhyay, Ashutosh Shrivastava.
      Temozolomide (TMZ) is a frontline chemotherapeutic agent for glioblastoma multiforme (GBM); however, approximately half of patients develop resistance to therapy. This study investigates the role of altered cellular bioenergetics and metabolism in the acquired TMZ resistance. Using untargeted metabolomics, we explored the metabolic rewiring in TMZ-resistant GBM cells and identified key alterations in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, and amino acid metabolism, all might be linked to cellular proliferation. Our findings suggest that while glycolysis remains important, increased TCA cycle activity contributes to the drug resistance, supported by increased levels of mitochondrial mass and mitochondrial membrane potential. We observed significantly elevated glutamine levels, which may enhance mitochondrial activity, thereby supporting increased energy production. Furthermore, resistant cells exhibited enhanced NRF2 level in parallel with higher levels of antioxidants, including glutathione and catalase enzyme, and a concomitant decrease in the level of its negative regulator, KEAP1. These factors collectively may contribute to drug resistance by mitigating oxidative stress. These findings indicate that mitochondrial metabolic reprogramming and NRF2/KEAP1-mediated antioxidant defense mechanisms play a crucial role in TMZ resistance, and targeting these pathways may offer a novel strategy to overcome resistance in GBM therapy.
    Keywords:  drug resistance; glioblastoma multiforme; mitochondria metabolism; oxidative stress; temozolomide
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00734
  12. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2508707122
    Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
    Brooks P Leitner, Andin E Fosam, Won D Lee, Kaylee Zilinger, Susana C B R Nakandakari, Xinyi Zhang, Rafael C Gaspar, Wanling Zhu, Curtis J Perry, Joshua D Rabinowitz, Rachel J Perry.
      Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor-host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.
    Keywords:  breast cancer; exercise; melanoma; tumor metabolism
    DOI:  https://doi.org/10.1073/pnas.2508707122
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