bims-cesemi 2026-05-31 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2026–05–31
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor

Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.
Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
Exploring Replicative Senescence and Oxidative Stress-Induced Remodelling of Mitochondrial-Associated Membranes in Human Skin Fibroblasts.
ITPR1 Maintains Mitochondrial Redox Homeostasis to Drive Glioblastoma Progression Through Recruitment and Activation of DRP1.
Transcription-independent induction of rapid-onset senescence is integral to healing.
Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.
Response to: Limitations of the p16-3MR mouse model for detecting and eliminating senescent cells.
The MCU-MECOM Axis Orchestrates Glioblastoma Progression by Remodeling Mitochondrial Dynamics and Quality Control via MAMs.

Cell Death Differ. 2026 May 27.

Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.

Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.

Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.

DOI: https://doi.org/10.1038/s41418-026-01769-8
Nat Commun. 2026 May 25.

Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.

I-Chi Lee, Po-Hsuan Lai, Chen-Wei Tsai, Yung-Chi Tu, Yu-Chen Huang, Wei-Chen Chen, Ming-Feng Tsai.

The mitochondrial Ca2+ uniporter mediates mitochondrial Ca2+ uptake to regulate cellular bioenergetics, Ca2+ signaling and survival, but excessive activity triggers Ca2+ overload and tissue injury. Cells counter this threat by expressing MCUb, a paralog of the uniporter's pore-forming MCU subunit, to attenuate uniporter activity. Despite harboring the conserved Ca2+-coordinating DIME motif, MCUb paradoxically lacks conductance, a defining yet enigmatic feature underlying its uniporter-inhibitory role. Here, we demonstrate that MCUb's non-conductivity stems from its inability to bind EMRE, a subunit essential for uniporter function, and that its N-terminal domain (NTD) exerts autoinhibition. Reinstating EMRE binding and relieving NTD-mediated inhibition rebuild Ca2+ conductance in MCUb, reaching ~80% of MCU activity. Wild-type MCUb exhibits ~30% of the inhibitory capacity of a pore-disrupting E249A variant, indicating that MCUb is a modest, rather than potent, negative regulator. These findings reveal how MCU-MCUb paralog divergence endows the uniporter with regulatory plasticity to fine-tune mitochondrial Ca2+ homeostasis.

DOI: https://doi.org/10.1038/s41467-026-73711-y
Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]

Mitochondria-lysosome coupling contributes to lysosome acidification and aging.

Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.

  Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.

Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification

DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
Biomolecules. 2026 May 11. pii: 704. [Epub ahead of print]16(5):

Exploring Replicative Senescence and Oxidative Stress-Induced Remodelling of Mitochondrial-Associated Membranes in Human Skin Fibroblasts.

Anne-Laure Bulteau, Gallic Beauchef, Stéphanie Chanon, Aurélie Vieille-Marchis, Julien Chlasta, Gaël Runel, Juliette Sage, Tanesha Naiken, Lauren Sobilo, Elodie Bossard, Lorene Gourguillon, Carine Nizard, Karl Pays, Laurence Canaple, Beatrice Morio.

  (1) Background: Calcium transfer between the endoplasmic reticulum (ER) and mitochondria through the IP3R-VDAC1 complex at mitochondria-associated ER membranes (MAMs) is essential for cellular homeostasis. Alterations in this signalling axis have been implicated in ageing and cellular senescence. (2) Methods: We developed an in vitro human dermal fibroblast (HDF) model combining replicative senescence and acute oxidative stress to investigate the role of ER-mitochondria coupling in skin ageing and to enable biomolecule screening. (3) Results: In situ proximity ligation assays revealed that replicative senescence significantly increased the number of VDAC1/IP3R complexes per cell (+85% and +72%, p < 0.01), together with elevated cellular reactive oxygen species (+47% and +74%, p < 0.05). Consistently, acute oxidative stress (50 µM t-BHP, 30 min) rapidly increased VDAC1/IP3R complexes (+48%, p < 0.001) and intra-mitochondrial calcium levels (+19%, p < 0.001). These effects persisted for 24 h post-treatment and were associated with impaired mitochondrial function (-27% in the Bioenergetic Health Index, p < 0.05). We also established a flexibility index capturing both acute and long-term adaptations and detecting the protective effects of an orchid extract. (4) Conclusions: ER-mitochondria coupling disruption via the IP3R-VDAC1 complex may contribute to oxidative stress-induced senescence and represent a key mechanism in extrinsic skin ageing.

Keywords:  Bioenergetic Health Index; cytoskeleton physical properties; intra-mitochondrial calcium; mitochondria-ER contact sites; oxidative stress; skin ageing

DOI:  https://doi.org/10.3390/biom16050704
Antioxidants (Basel). 2026 Apr 26. pii: 550. [Epub ahead of print]15(5):

ITPR1 Maintains Mitochondrial Redox Homeostasis to Drive Glioblastoma Progression Through Recruitment and Activation of DRP1.

Shuyan Luo, Mei Tao, Sihan Li, Xingbo Li, Qian Jiang, Quanji Wang, Zihan Wang, Lv Zhou, Kai Shu, Zhuowei Lei, Yimin Huang, Ting Lei.

  Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca2+) signaling at endoplasmic reticulum (ER)-mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in GBM remain unclear. Methods: ITPR1 expression was analyzed using single-cell and bulk RNA sequencing (RNA-seq) datasets and validated by immunohistochemistry and survival analyses. Functional studies were conducted using genetic silencing or CRISPR-mediated activation of ITPR1, combined with DRP1 knockdown, Ca2+ imaging, transmission electron microscopy, co-immunoprecipitation, mitochondrial fractionation, and mitochondrial functional assays. Therapeutic efficacy was evaluated in orthotopic GBM xenograft models treated with 2-aminoethoxydiphenyl borate (2-APB), temozolomide (TMZ), or their combination. Results: ITPR1 was enriched in mesenchymal-like malignant cell states and associated with higher tumor grade, recurrence, and poor prognosis. ITPR1 knockdown suppressed GBM cell proliferation and tumor growth while promoting intrinsic apoptosis. Mechanistically, loss of ITPR1 impaired ER-to-mitochondria Ca2+ transfer, disrupted ER-mitochondria contacts, and altered mitochondrial ultrastructure. This was accompanied by reduced DRP1 Ser616 phosphorylation and mitochondrial recruitment, as well as decreased autophagy and mitophagy activity. Consequently, ITPR1 knockdown led to mitochondrial depolarization, increased mitochondrial reactive oxygen species (ROS) accumulation, and activation of mitochondria-dependent apoptosis. Conversely, DRP1 knockdown attenuated the mitochondrial and pro-survival effects induced by ITPR1 overexpression. In vivo, combined treatment with 2-APB and TMZ resulted in greater tumor suppression and prolonged survival compared with either treatment alone, accompanied by increased apoptosis and reduced proliferation in tumor tissues. Conclusions: ITPR1 promotes GBM progression by sustaining ER-mitochondria Ca2+ coupling and DRP1-dependent mitochondrial quality control, thereby maintaining mitochondrial homeostasis and cell survival. Targeting inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling with 2-APB enhances the therapeutic efficacy of TMZ, suggesting that ITPR1-centered Ca2+ signaling may represent a potential therapeutic vulnerability in aggressive GBM.

Keywords:  2-APB; DRP1; ITPR1; glioblastoma; mitophagy; temozolomide

DOI:  https://doi.org/10.3390/antiox15050550
Nat Cell Biol. 2026 May 28.

Transcription-independent induction of rapid-onset senescence is integral to healing.

Karla Valdivieso, Tomaz Rozmaric, Stella Victorelli, Vaibhav Jadhav, Nadja Anneliese Ruth Ring, Sylwia Machcińska-Zielińska, Barbara Schädl, Helene Dworak, Eirini Klinaki, Ines Fischer, Agnieszka Gadecka, Iryna Moskalevska, Sara Kostrebic, Michaela Kienberger, Edyta Marzec, Christina Efraimoglou, Alessia Zanchetta, Julien Cherfils-Vicini, Oleh Lushchak, Andreas Löscher, Thomas Kolbe, Maik Dahlhoff, Nicholas E Pirius, Aniko Gutasi, Sarolta Takacs, James Ferguson, Bruno K Podesser, Paul Slezak, David Monroe, Bin Zhou, Sundeep Khosla, Johannes Grillari, Heinz Redl, Diana Jurk, Mikolaj Ogrodnik.

Cellular senescence plays key roles in tissue repair, tumour suppression and ageing. Here we identify a rapid, transcription‑independent senescence response in skin following injury. Within minutes to hours after wounding, skin cells at the edge of injury display hallmark features of senescence. This response involves the utilization of pre‑existing Cdkn1a mRNA through the removal of nuclear export inhibitors, which enables Cdkn1a transcript translation and rapid p21 protein accumulation. These cells enter stable cell‑cycle arrest and secrete pro‑migratory and pro‑inflammatory factors that promote tissue repair, including re‑epithelialization. Experimental suppression of this rapid senescence, either genetically or pharmacologically, markedly delays wound closure, whereas inhibition during later phases of repair has no effect. Our findings establish rapid‑onset senescence as a mechanistic requirement for efficient tissue regeneration.

DOI: https://doi.org/10.1038/s41556-026-01948-2
Sci Adv. 2026 May 29. 12(22): eaed5255

Multicellular senescence impairs skeletal muscle recovery following disuse in aging.

Paul-Emile Bourrant, Elena M Yee, Zachary J Fennel, Robert J Castro, Chad M Skiles, Jonathan J Petrocelli, Naomi M M P de Hart, Lisa A Lesniewski, Anna E Beaudin, Katsuhiko Funai, Christopher S Fry, Micah J Drummond.

Aged skeletal muscle has a diminished capacity to recover after disuse. Although muscle regrowth requires coordinated interactions between immune and progenitor cells, the mechanisms of impaired remodeling in aged skeletal muscle remain poorly understood yet possibly involve the accumulation of senescent cells. We used a flow cytometry approach coupled with scRNAseq to determine the muscle senescent cell identity and transcriptional landscape during skeletal muscle recovery following disuse atrophy. Young and aged mice underwent 14 days of hindlimb unloading followed by reloading (7 or 14 days). At recovery, old mice showed smaller myofibers and abnormal muscle macrophage dynamics corresponding to greater collagen content. These outcomes coincided with elevated markers of muscle senescence (p21 and γH2AX) and increased SPiDER-β-Gal+ cells, which inversely correlated with muscle mass. Single-cell resolution of SPiDER+ cells unmasked several senescent interstitial muscle vascular and stromal populations. Senescent interstitial cell populations were enriched in aged muscle and displayed a senescence-associated secretory phenotype (SASP) across multiple stromal, vascular, and immune cell types. Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse. These findings identify a multicellular senescence environment within the muscle interstitial niche as a hallmark of impaired muscle recovery following disuse.

DOI: https://doi.org/10.1126/sciadv.aed5255
Nature. 2026 May 27.

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.

Apoorva Uboveja, Baixue Yang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Julie A Disharoon, Richard S Fang, Evan Levasseur, Miho Naruse, Zhentai Huang, Emily Megill, Daniel S Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Sarah Graff, Ellen De Pieri, Andrea Andress Huacachino, Frank P Vendetti, Jeff Danielson, Erika S Dahl, Jennifer L Pennise, Esther Elishaev, Alison Jaccard, Lauren Borho, Miriam D Post, Kristine Cooper, Francesmary Modugno, Nadine Hempel, Wayne Stallaert, Christopher J Bakkenist, Simone Sidoli, Kathryn E Wellen, Benjamin G Bitler, David T Long, Nathaniel W Snyder, Katherine M Aird.

Homologous recombination (HR) deficiency increases sensitivity to DNA-damaging agents that are commonly used to treat cancer1. In HR-proficient cancers, the metabolic mechanisms that drive response or resistance to DNA-damaging agents remain unclear. Here we have identified that depletion of α-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases2 (αKGDDs), and previous work has focused almost exclusively on the demethylase functions of αKGDD. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that trimethyllysine hydroxylase epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for the survival of HR-proficient cells in the presence of DNA-damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation and was non-redundant with other nucleo-cytosolic acetyl-CoA-generating pathways. The increase in histone acetylation by means of the αKG-carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This study demonstrates for the first time, to our knowledge, that αKG affects site-specific histone acetylation and provides a mechanism of HR proficiency through carnitine synthesis. Moreover, these data provide a metabolic avenue for inducing HR deficiency and promoting sensitivity to DNA-damaging agents.

DOI: https://doi.org/10.1038/s41586-026-10584-7
EMBO Rep. 2026 May 28.

Response to: Limitations of the p16-3MR mouse model for detecting and eliminating senescent cells.

Boshi Wang, Jamil Nehme, Marco Demaria.

DOI: https://doi.org/10.1038/s44319-026-00801-9
Int J Biol Sci. 2026 ;22(10): 5054-5082

The MCU-MECOM Axis Orchestrates Glioblastoma Progression by Remodeling Mitochondrial Dynamics and Quality Control via MAMs.

Xiaodong Li, Yaoliang Wang, Feifei Wu, Xin Huang, Ziwei Ni, Guangzhen Xu, Weizhong Wang, Jingjing Tie, Yunqiang Huang, Yuze Sun, Zhenhua Wang, Shujiao Li, Qianwen Zheng, Yuxuan Liu, Yousheng Wu, Chengrong Gong, Qingdong Guo, Yanling Yang, Yayun Wang.

  Glioblastoma (GBM) exhibits metabolic plasticity, relying on mitochondrial oxidative phosphorylation (OXPHOS) to support migration and therapy resistance. Although mitochondrial calcium overload typically induces apoptosis, GBM cells maintain viability under high calcium conditions. The structural and metabolic coupling mechanisms underlying this adaptation remain incompletely understood. Here, we identify a mitochondria-associated membranes (MAMs) regulatory axis driven by a positive feedback loop between the mitochondrial calcium uniporter (MCU) and the transcription factor MECOM. Using multi-omics profiling, time-resolved functional assays, and mitochondrial transfer experiments, we show that MCU-mediated calcium influx expands MAMs without triggering cell death. This influx initiates adaptive mitochondrial cristae remodeling via the Mic10/Mic60 complex and activates selective mitophagy. Pharmacological blockade and autophagy-rescue experiments (using si-ATG5 and chloroquine) indicate that this mitophagy-dependent quality control promotes tumor migration and buffers reactive oxygen species (ROS) to sustain OXPHOS capacity. Targeting the MCU-MECOM axis induces metabolic suppression and reduces glioma cell viability. To translate these findings into a diagnostic application, we developed MAMs-Net, a deep-learning framework for the automated quantification of MAMs ultrastructure from transmission electron microscope (TEM) images. In an independent external validation cohort, MAMs-Net achieved an AUC of 0.95 for glioma pathological stratification. This study characterizes an MCU-MECOM structural-metabolic circuit that supports GBM survival under calcium overload, identifying a potential therapeutic target and providing a pathophysiologically interpretable, AI-driven tool for glioma evaluation.

Keywords:  Glioblastoma; MAMs; MAMs-Net; MCU; MECOM

DOI:  https://doi.org/10.7150/ijbs.127940