bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–06–21
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
  2. The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
  3. Senescence as a regulatory mechanism in skeletal muscle repair in young mice.
  4. Dissecting mitochondria-nucleus contact sites using SPLICS reveals a distributed and dynamic tethering network.
  5. Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
  6. Conformational landscape and ligand-dependent clustering of the human type 2 IP3 receptor.
  7. Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.
  8. Lysosomal TMEM165 remodels calcium signaling to drive hypoxia adaptation and tumor progression.
  9. Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
  10. Gene therapy for aging and longevity.
  1. NPJ Aging. 2026 Jun 18.
    Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
    Jun-Wei B Hughes, Akshay Pujari, Anja Sandholm, Duncan Croll, Lea Baskin Monk, Isaac Joshua, Rachel Butterfield, Corrigan Horton, Kevin Schneider, Fiona Senchyna, Ian Brown, Zhixin A Zhang, Ana L Coelho, Tsung-Che Ho, Hideto Deguchi, Ryo Higuchi-Sanabria, Claude Jourdan Le Saux, Stefanie Deinhardt-Emmer, Lisa M Ellerby, Alberto C Vitari, David Furman, Cory M Hogaboam, Alex Laslavic, Pierre-Yves Desprez, Marco Quarta, Judith Campisi.
      Cellular senescence is a highly heterogeneous state of cell stress response that deleteriously accumulates with age and contributes to age-related dysfunction. While the heterogeneity across cell types is well documented, variation within the same cell type is only beginning to be understood. Here, we show primary human lung fibroblasts from either donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair and cytokine and chemokine responses. We combine our healthy and IPF senescent gene expression datasets to develop a novel gene signature of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine, and chemokine targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.
    DOI:  https://doi.org/10.1038/s41514-026-00388-4
  2. Cell Metab. 2026 Jun 15. pii: S1550-4131(26)00193-2. [Epub ahead of print]
    The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
    Luigi Ferrucci, Stefano Donega, Allison B Herman, Rafael de Cabo, Myriam Gorospe.
      Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis. The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.
    Keywords:  extracellular matrix; hypoperfusion; mitochondrial dysfunction; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.008
  3. Am J Physiol Cell Physiol. 2026 Jun 18.
    Senescence as a regulatory mechanism in skeletal muscle repair in young mice.
    Amanda L Johnson, Ryan T Bevington, Gianni Parise.
      Senescence is broadly considered an age-related phenomenon; however, it also been implicated in normal tissue repair and wound healing. Skeletal muscle repair is a complex process that requires the coordination of several different cell populations but the role of senescence in skeletal muscle repair has yet to be fully elucidated. We hypothesize that senescence serves as a control mechanism throughout the regenerative process and the removal of senescent cells through senolytics will negatively impact the repair process in young mice. Briefly, young mice were exposed to either (a) vehicle (VEH), receiving only a cardiotoxin (CTx) injection in one hindlimb or (b) 7 days of senolytic treatment (SEN) pre-CTx and 3x/week for 4 weeks post-CTx. Dasatinib + Quercetin (D+Q) was used to selectively eliminate senescent cells. There were no significant differences between groups in functional measures such as hindlimb grip strength and cross-sectional area. eMHC+ fibers remained elevated at D28 in the SEN group. Macrophage infiltration was twice as high in the SEN group compared to VEH at D7. Satellite cell quantity and fibrotic area were significantly increased at D14 in the SEN group compared to VEH. We conclude that reducing senescent cells during muscle repair in young mice significantly altered the kinetics of muscle repair. Therefore, senescent cells may act as a regulatory mechanism in skeletal muscle to orchestrate the activity of the different cell populations involved in repair and regeneration such as immune cells, satellite cells, and fibrotic cells.
    Keywords:  Repair; Satellite cells; Senescence; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00154.2026
  4. Biol Direct. 2026 Jun 17.
    Dissecting mitochondria-nucleus contact sites using SPLICS reveals a distributed and dynamic tethering network.
    Adamantia Deligiannopoulou, Lucia Barazzuol, Caterina Peggion, Elena Poggio, Michelangelo Campanella, Marisa Brini, Tito Calì.
      Mitochondria-nucleus contact sites (also known as nucleus-associated mitochondria, NAMs) are emerging as important platforms for inter-organelle communication; however, their molecular organisation and regulation remain poorly understood. Here, we use split-GFP-based contact site sensors (SPLICSS-P2ANU-MT) to quantitatively dissect the contribution of candidate tethering proteins to the formation of short-range mitochondria-nucleus contacts in HeLa cells. Through systematic overexpression and downregulation approaches, we identify TOM70, MFN2, AKAP95, and the catalytic subunit of PKA as positive modulators of contact formation when individually overexpressed. In contrast, loss-of-function experiments reveal a selective role for TOM70, whose downregulation significantly reduces contact site abundance, whereas depletion of other candidates has limited effects. These results suggest that mitochondria-nucleus contacts are not maintained by single dominant tethers but instead rely on the coordinated contribution of multiple proteins. To further investigate cooperative mechanisms, we performed co-expression experiments. Among the combinations tested, TSPO in conjunction with either the regulatory or catalytic subunits of PKA significantly increased contact site formation, indicating that specific protein partnerships are required to establish functional tethering. Overall, our data support a model in which mitochondria-nucleus contact sites are heterogeneous and regulated by a network of interacting factors rather than a single structural component. These findings highlight the complexity of inter-organelle communication and underscore the importance of dissecting both individual and combinatorial roles of contact site components to understand their functional relevance.
    Keywords:  NAM; Organelle communication; Protein kinase A (PKA) and TSPO; SPLICSS; TOM70
    DOI:  https://doi.org/10.1186/s13062-026-00870-9
  5. Cell Metab. 2026 Jun 17. pii: S1550-4131(26)00240-8. [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.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.014
  6. Nat Commun. 2026 Jun 19.
    Conformational landscape and ligand-dependent clustering of the human type 2 IP3 receptor.
    Caifeng Liu, Yu-Jing Lan, Max G Kushner, Qingyu Tang, Erkan Karakas.
      Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are tetrameric ER Ca2+ channels that shape intracellular Ca2+ signaling in response to IP3, regulating diverse physiological processes. The structural basis for subtype-specific regulation among the three subtypes (IP3R-1-3) remains incompletely understood due to the lack of IP3R-2 structures. Here, we report cryo-electron microscopy (cryo-EM) structures of human IP3R-2 in distinct conformations in the presence and absence of IP3, Ca2+, and ATP. These structures define the conformational landscape of IP3R-2, delineate ligand-binding interactions, and reveal shared architectural features alongside isoform-specific differences. We also resolve ligand-dependent IP3R-2 assemblies, identifying a conformation-dependent inter-channel interface. Live-cell imaging demonstrates that IP3R-2 undergoes clustering following ligand-induced Ca2+ release, and disruption of this interface selectively abolishes clustering without impairing channel activity. Together, these findings provide a structural framework for human IP3R-2 and establish a mechanism linking ligand-dependent conformational changes to inter-channel interactions and post-activation cellular clustering.
    DOI:  https://doi.org/10.1038/s41467-026-74494-y
  7. Nat Aging. 2026 Jun;6(6): 1281-1297
    Profiling the molecular and physiological effects of senolytic treatment on aged mice identifies immune, fibrotic and metabolic remodeling.
    Jing Hou, Kai-Xuan Chen, Qiao-Ni Xiao, Chen Hu, Jie Wei, Yang-Zi Jiang, Ling Liu, Chen He, Mei Huang, Yu-Rui Jiao, Xiang Tang, Nan-Yu Zou, Wen-Zhen He, Yu-Chen Sun, Yue-Ying Zhou, Xi Huang, Chao Zeng, Guang-Hua Lei, Yi-Lun Wang, Chang-Jun Li.
      Although senolytics such as dasatinib and quercetin (D+Q) show promise in modulating aging, their tissue-specific efficacy and optimal intervention timing remain poorly understood. Given D+Q's potential off-target effects, incomplete senescent cell clearance and associated hematologic side effects, we performed an unbiased multitissue single-cell analysis in aged mice across different aging phenotypes and tissue contexts. Here through integrative transcriptomics, single-cell technologies, histopathology and molecular profiling, we investigated the influence of D+Q treatment on aging-related phenotypes at the tissue and cellular levels. Specifically, D+Q remodeled immunity by enhancing immune cell function and maintaining population stability, alleviated tissue inflammation and improved metabolic profiles. Furthermore, intervention initiated during early aging and prolonged treatment showed a greater tendency to mitigate readouts of aging compared to shorter, late-stage treatment. Our findings reveal that D+Q systematically attenuates several aging hallmarks in a tissue- and cell-type-specific manner, and support the possibility that early-initiated, long-term intervention may amplify efficacy.
    DOI:  https://doi.org/10.1038/s43587-026-01130-1
  8. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2532309123
    Lysosomal TMEM165 remodels calcium signaling to drive hypoxia adaptation and tumor progression.
    Yu Zeng, Meiting Chen, Yu Cao, Yan Huang, Xingguo Yang, Qian Jiang, Jiamin Huang, Yu Chen, Xin Du, Wenping Zeng, Qiankun Mao, Huafeng Zhang, Li Wang, Xiaomei Li, Canjun Li, Lili Qu, Chunlei Cang.
      Hypoxia is a common stress encountered by animal tissues during development, physiology, and disease. To cope with hypoxic stress, cells remodel metabolic and signaling networks to preserve viability and function. Lysosomes serve as central hubs for metabolic control and intracellular signaling, yet their role in hypoxic adaptation remains unclear. Here, we identify the lysosomal calcium transporter TMEM165 as a hypoxia-responsive regulator of cellular homeostasis. Under hypoxic conditions, TMEM165 expression increases, promoting calcium redistribution from the endoplasmic reticulum to lysosomes and expanding lysosomal calcium storage capacity. TMEM165 activation regulates autophagy and senescence through the AMPK-mTOR and ERK/p21 signaling pathways, respectively. In glioma, high TMEM165 expression correlates with poor prognosis, whereas its depletion suppresses glycolysis, proliferation, and tumor progression. These findings establish TMEM165 as a lysosomal hypoxia-responsive protein that integrates calcium signaling with metabolic and stress-response pathways, revealing a mechanistic link between oxygen availability, lysosomal function, and tumor adaptation.
    Keywords:  TMEM165; calcium signaling; cancer; hypoxia; lysosome
    DOI:  https://doi.org/10.1073/pnas.2532309123
  9. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2530774123
    Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
    Marine Tessier, Zeinab Hamze, Nathalie Bonello-Palot, Nathalie Roeckel-Trévisiol, Nathalie Da Silva, Ilian Verlet, Natacha Broucqsault, Karine Bertaux, Emilien Delmont, Shahram Attarian, Marc Bartoli, Valérie Delague, Bernard L Schneider, Nathalie Bernard-Marissal.
      Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
    Keywords:  Charcot–Marie–Tooth disease; MFN2; endoplasmic reticulum; gene therapy; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2530774123
  10. Trends Mol Med. 2026 Jun 17. pii: S1471-4914(26)00116-4. [Epub ahead of print]
    Gene therapy for aging and longevity.
    Stacia P A Everts, Michael Florea, João Pedro de Magalhães.
      Aging affects virtually all organs and biological processes, and age-related diseases remain the leading causes of death worldwide. Genetic factors play a central role in modulating lifespan, and discoveries in the genetic manipulation of the aging process in animal models have transformed our perception of aging. However, translating these findings into clinical therapies remains challenging. Recent breakthroughs demonstrate that gene therapies can directly target aging mechanisms. Single-gene therapies have ameliorated multiple age-related pathologies, such as pediatric Parkinson disease. In this review, we discuss recent advances and prospects for developing gene therapies for aging and age-related diseases, highlighting potential targets, delivery strategies, cellular rejuvenation, and lessons from long-lived species. Despite remaining challenges, longevity gene therapy offers a promising avenue to reprogram aging and delay age-related decline.
    Keywords:  AAV; geroscience; healthspan; lifespan; rejuvenation
    DOI:  https://doi.org/10.1016/j.molmed.2026.05.007
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