bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–08–02
thirteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
  2. Mitochondrial metabolism and epigenetic crosstalk drive SASP.
  3. Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
  4. The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
  5. Signatures of aging and disease in a single organelle.
  6. CDK4/6 Inhibitor-Induced Senescence in Cancer: Mechanisms and Therapeutic Implications.
  7. Pannexin1 promotes cellular senescence by triggering mtDNA release to activate the cGAS-STING pathway.
  8. Genomic, epigenomic and transcriptomic regulation of cellular senescence.
  9. ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.
  10. Nicotinamide Improves Skin Photoaging in Mice by Delaying Cellular Senescence and Suppressing the Senescence-Associated Secretory Phenotype.
  11. Fatty acid metabolism in glioma: a review of novel targets and therapeutic strategies.
  12. Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
  13. Cellular senescence: the "hidden driver" in chronic inflammatory skin disorders.
  1. Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00845-4. [Epub ahead of print]45(8): 117767
    Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
    Arijita Ghosh, David Weaver, Chi Li, Gyӧrgy Hajnóczky.
      Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP3 receptor Ca2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca2+ transfer without changing ER Ca2+ release, despite attenuating mitochondrial Ca2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca2+ signal propagation into the mitochondria.
    Keywords:  Bcl-xL; CP: cell biology; CP: metabolism; ERMC; IP3R; calcium signaling; endoplasmic reticulum; local Ca(2+) transfer; mitochondria; organellar crosstalk
    DOI:  https://doi.org/10.1016/j.celrep.2026.117767
  2. Nature. 2026 Jul 29.
    Mitochondrial metabolism and epigenetic crosstalk drive SASP.
    Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.
      Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.
    DOI:  https://doi.org/10.1038/s41586-026-10791-2
  3. Cell Rep. 2026 Jul 31. pii: S2211-1247(26)00921-6. [Epub ahead of print]45(8): 117843
    Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
    Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.117843
  4. Nat Aging. 2026 Jul 30.
    The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
    Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.
      Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.
    DOI:  https://doi.org/10.1038/s43587-026-01172-5
  5. Science. 2026 Jul 30. 393(6810): 461
    Signatures of aging and disease in a single organelle.
    Jeeyoon Na, Anne Brunet.
      Changes in lysosomal metabolites are associated with both aging organs and lysosomal storage diseases.
    DOI:  https://doi.org/10.1126/science.aej5901
  6. Cancers (Basel). 2026 Jul 08. pii: 2192. [Epub ahead of print]18(14):
    CDK4/6 Inhibitor-Induced Senescence in Cancer: Mechanisms and Therapeutic Implications.
    Simin Elif Türker, Marco Demaria, Boshi Wang.
      Pharmacological cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have reshaped the treatment landscape of HR-positive, HER2-negative (HR+/HER2-) breast cancer and are increasingly being explored across diverse malignancies. By preventing retinoblastoma (RB) phosphorylation and enforcing G1-S cell cycle arrest, these agents achieve durable tumour control with a more favourable toxicity profile than conventional chemotherapy. Beyond their canonical cytostatic effects, prolonged CDK4/6 inhibitor treatments induce cellular senescence, a stable, proliferative arrest accompanied by profound transcriptional, epigenetic, and secretory changes. This review summarises current knowledge on CDK4/6 inhibitor-induced senescence in both cancer and normal cells as a central biological mechanism that links tumour suppression and microenvironmental remodelling. Importantly, this process is highly context-dependent, differing between tumour and non-malignant cells, with a distinct senescence-associated secretory phenotype (SASP) that shapes immune responses and tissue homeostasis. We also discuss how CDK4/6 inhibitor-induced senescence influences the tumour microenvironment by modulating immune surveillance, stromal interactions, and cancer cell plasticity. Finally, we examine emerging resistance mechanisms and rational combination strategies for CDK4/6 inhibitors, including targeting compensatory signalling pathways, immune checkpoint blockades, and senescence-directed sequential therapies. Collectively, CDK4/6 inhibitor-induced senescence represents both a challenge and a therapeutic opportunity, underscoring the need to integrate cell cycle control with the modulation of cellular states.
    Keywords:  CDK4/6 inhibitors; SASP; combination therapies; senescence
    DOI:  https://doi.org/10.3390/cancers18142192
  7. Biochim Biophys Acta Mol Basis Dis. 2026 Jul 28. pii: S0925-4439(26)00251-6. [Epub ahead of print] 168388
    Pannexin1 promotes cellular senescence by triggering mtDNA release to activate the cGAS-STING pathway.
    Jiaqi Li, Xin Zhao, Yanting Shen, Liuwei Huang, Jie Guo, Jun Wang.
      Cellular senescence is a pivotal driver of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). We previously identified Pannexin 1 (Panx1) as an endoplasmic reticulum (ER)-resident calcium (Ca2+) leak channel that promotes renal tubular senescence; however, the precise downstream effectors remain elusive. Here, we establish a novel mechanistic link between Panx1 and the cGAS-STING pathway. We show that Panx1 triggers cGAS-STING activation by facilitating the cytosolic release of mitochondrial DNA (mtDNA). Mechanistically, we establish a strict hierarchical relationship in this process: the opening of the mitochondrial permeability transition pore (mPTP) serves as a mandatory prerequisite for BAX translocation to mitochondria, which together orchestrate the efflux of immunogenic mtDNA. Cytosolic mtDNA accumulation engages the cGAS-STING pathway, driving the senescence-associated secretory phenotype (SASP) through NF-κB signaling while concurrently activating IRF3-mediated interferon responses. Genetic or pharmacological blockade of the Panx1-mPTP-BAX-cGAS signaling cascade effectively attenuates the senescent phenotype in human tubular epithelial cells. In mouse models of renal ischemia/reperfusion injury, pharmacological inhibition of Panx1 or STING alleviates renal tubular senescence, fibrosis, and the pathological progression from AKI to CKD. Our findings define the Panx1/mPTP/BAX/cGAS-STING axis as a fundamental driver of cellular senescence, offering refined therapeutic targets for mitigating senescence-associated kidney pathologies.
    Keywords:  BAX; Cellular senescence; Pannexin1; cGAS-STING; mPTP; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168388
  8. Nat Rev Genet. 2026 Jul 29.
    Genomic, epigenomic and transcriptomic regulation of cellular senescence.
    Rahagir Salekeen, Tra L Kieu, Paul D Robbins, Laura J Niedernhofer, Linshan Laux.
      Cellular senescence is a complex, highly regulated cell state induced by cellular damage and stress. Senescence is central to many areas of biology, with roles in tumour suppression, tissue regeneration, antiviral defence and diverse age-related pathologies. Senescence is characterized by stable cell cycle arrest, metabolic alterations, chromatin remodelling and the secretion of pro-inflammatory and tissue-modifying factors that are collectively termed the senescence-associated secretory phenotype. Recent technological advances, including new genetic models, single-cell and spatial multi-omics platforms and machine-learning approaches, promise to enable the phenotyping, tracing and manipulation of senescent cells with unprecedented precision and resolution. This Review defines our current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication. We also emphasize key challenges in distinguishing senescence from other cell fates and the need for next-generation biomarkers to capture the varied phenotypes and functions of senescent cells.
    DOI:  https://doi.org/10.1038/s41576-026-00982-y
  9. Adv Sci (Weinh). 2026 Jul 30. e76972
    ATL2 Recruits TRAK1 to Promote Mitochondrial Transport at ER-Mitochondria Contact Sites.
    Yiru Cheng, Peiyuan Chai, Xiayuhe Pei, Yiwen Chen, Xiaoshuai Huang, Bei Liu, Yiqian Wu, Junlin Teng, Pengli Zheng, Jianguo Chen.
      Mitochondrial transport and distribution are crucial for cellular homeostasis, yet whether and how they are regulated by endoplasmic reticulum (ER)-mitochondria contact sites remains unclear. Here, we demonstrate that the ER protein atlastin-2 (ATL2) orchestrates mitochondrial transport and distribution by promoting assembly of the transport machinery at ER-mitochondria contact sites. Mechanistically, ATL2 recruits the adaptor trafficking kinesin-binding protein 1 (TRAK1) to the ER membrane, strengthening the interaction of TRAK1 with the mitochondrial transport adaptor MIRO1 to promote anterograde mitochondrial transport. Loss of ATL2 disrupts this process, leading to perinuclear mitochondrial clustering. We further find that ATL2 stabilizes ER-mitochondria contact sites by interacting with MFN2, providing a platform for mitochondrial transport complex assembly. Moreover, in hypoxia, ATL2 is ubiquitinated at lysine 567 by the E3 ligase SYVN1, leading to its degradation and a resulting defect in mitochondrial distribution. Our findings elucidate a novel ER-mediated mechanism for mitochondrial transport.
    Keywords:  ATL2; ER–mitochondria contact sites; TRAK1; hypoxia; mitochondrial transport
    DOI:  https://doi.org/10.1002/advs.76972
  10. Curr Issues Mol Biol. 2026 Jun 27. pii: 661. [Epub ahead of print]48(7):
    Nicotinamide Improves Skin Photoaging in Mice by Delaying Cellular Senescence and Suppressing the Senescence-Associated Secretory Phenotype.
    Xin-Yue Tang, Ke-Jin Lu, Rui Zhu, Yue Gao, Dong-Yan Wei, Xi-Yu Zhang, Yi-Cheng Ma, Fei-Fei Wang, Cheng-Gang Zou.
      Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD+), and NAD+ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains unclear. In this study, the multi-omics analysis revealed that insufficient nicotinamide metabolism may be associated with a decrease in NAD+ synthesis during skin aging. Importantly, we found that NAM has an ameliorating effect on the skin photoaging in mice. Supplementation with NAM restored the expression of the salvage-pathway enzymes and NAD+ consumers. In addition, the supplementation with NAM was shown to restore the expression of skin barrier-related proteins (ZO1 and E-cadherin) and collagen I, while reducing the expression of senescence markers (γ-H2AX, p53, and p21). Furthermore, we found that NAM effectively suppresses the senescence-associated secretory phenotype (SASP) factors' expression in skin photoaging. Our research reveals the dual role of NAM in attenuating skin photoaging, acting not only to delay cellular senescence but also to suppress the SASP.
    Keywords:  nicotinamide; senescence marker; senescence-associated secretory phenotype; skin photoaging
    DOI:  https://doi.org/10.3390/cimb48070661
  11. Chin Neurosurg J. 2026 Jul 31. pii: 23. [Epub ahead of print]12(1):
    Fatty acid metabolism in glioma: a review of novel targets and therapeutic strategies.
    Xiao Zhou, Di Wang, Wei Zhang, Guanzhang Li.
      Glioma is the most common primary malignant brain tumor in adults, among which glioblastoma (GBM) shows the highest degree of malignancy and the worst prognosis. Although standard therapeutic approaches, including surgical resection, radiotherapy, and chemotherapy, are routinely applied, the prognosis of glioma, especially GBM, remains poor. Metabolic rewiring is widely recognized as a major characteristic of malignant tumors and is especially evident in glioma. Recent studies have shown that fatty acid metabolic rewiring is a widespread feature of glioma and plays an important role in its pathogenesis and therapeutic resistance. Therefore, targeting metabolic reprogramming, particularly aberrant fatty acid metabolism, may have potential therapeutic implications in glioma. This review systematically synthesizes the molecular mechanisms underlying abnormal fatty acid metabolism in glioma pathogenesis and treatment responses. It also elucidates the regulatory networks governing key fatty acid metabolic pathways and integrates emerging strategies targeting these pathways to enhance the therapeutic sensitivity of glioma cells. Ultimately, this review aims to provide a conceptual framework and future research directions for overcoming the current limitations of glioma treatment through metabolic therapy.
    Keywords:  Fatty Acid Metabolism; Glioma; Metabolic Reprogramming; Therapeutic Resistance
    DOI:  https://doi.org/10.1186/s41016-026-00442-w
  12. Science. 2026 Jul 30. 393(6810): eady0832
    Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    DOI:  https://doi.org/10.1126/science.ady0832
  13. Immun Ageing. 2026 Jul 24. pii: 25. [Epub ahead of print]23(1):
    Cellular senescence: the "hidden driver" in chronic inflammatory skin disorders.
    Huifang Liang, Junqin Li, Kaiming Zhang.
      Chronic inflammatory skin disorders are characterized by persistent skin inflammation, impaired barrier function, and frequent recurrence, all of which substantially reduce patients' quality of life. Traditional studies attribute the pathogenesis of these diseases to immune dysregulation, whereas new evidence indicates that cellular senescence is a key risk factor and a mechanism underlying disease progression. Cellular senescence, defined by irreversible cell cycle arrest, is accompanied by a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and DNA damage. This review systematically outlines the hallmarks, regulatory mechanisms, and inducers of cellular senescence, elucidates its pathological role in representative inflammatory skin disorders, and evaluates emerging therapeutic strategies that target senescent cells. By elucidating the dynamic crosstalk between cellular senescence and inflammatory skin diseases, this review aims to identify novel therapeutic targets and provide new insights into their diagnosis, treatment, and prevention.
    Keywords:  Cellular senescence; Dermatoses; Inflammation; Relationship; Therapeutic strategies
    DOI:  https://doi.org/10.1186/s12979-026-00580-w
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