bims-cesemi 2026-08-30 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2026–08–30
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Timing-Dependent Clearance of p16-Positive Cells Mitigates Radiation-Induced Accelerated Aging.
Cryo-EM insights into isoform-specific properties of the IP3R2 channel.
Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
Mitochondria as central regulators of cancer progression and antitumor immunity.
Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
Cellular Senescence in Skin Wound Repair: Dual Roles and Senotherapeutic Interventions.

Aging Cell. 2026 Sep;25(9): e70693

Timing-Dependent Clearance of p16-Positive Cells Mitigates Radiation-Induced Accelerated Aging.

Karla Valdivieso, Melanie Weigand, Daniela G Costa, Gung Lee, Nick Pirius, Helene Martini, Shivangi Oberai, Christina Inman, Yi Zhu, Thomas von Zglinicki, Sundeep Khosla, Nathan LeBrasseur, João F Passos, Tamara Tchkonia, James L Kirkland, Diana Jurk.

  Genotoxic stress induced by cancer therapies is increasingly recognized as a driver of accelerated aging in long-term cancer survivors, yet the mechanisms responsible for the emergence of age-related dysfunction months to years after treatment remain poorly understood. Here, we use sublethal whole-body irradiation as a model of systemic genotoxic stress to test whether senescent cells contribute to the progression of post-therapy age-related dysfunction and whether the benefits of senescent cell clearance depend on the timing of intervention. Using the INK-ATTAC mouse model, we selectively eliminated p16Ink4a-positive cells either early (1 month) or later (4 months) after irradiation. Early clearance had no effect on lifespan or functional outcomes. In contrast, delayed clearance markedly reduced frailty, improved neuromuscular and cognitive function, restored blood-brain barrier integrity, improved hepatic metabolic dysfunction, and increased median survival, with the survival benefit being most evident in female mice. Mechanistically, irradiation induced an early p21Cip1-associated stress response and later accumulation of p16Ink4a-positive cells in the brain and liver, which was associated with inflammation and tissue dysfunction. Clearance of p16Ink4a-positive cells at the later stage attenuated these changes. Together, these findings identify p16Ink4a-positive cells as key drivers of the radiation-induced accelerated aging-like state that emerges progressively after genotoxic stress. They also show that the efficacy of senescence-targeted interventions depends on when treatment is initiated, with implications for improving long-term outcomes in cancer survivors.

Keywords:  BBB; aging; brain; cognition; irradiation; senescence; senolytic; therapy induced senescence

DOI:  https://doi.org/10.1111/acel.70693
Nat Commun. 2026 Jul 22. pii: 8929. [Epub ahead of print]17(1):

Cryo-EM insights into isoform-specific properties of the IP3R2 channel.

Mariah R Baker, Xiaoxuan Lin, Guizhen Fan, Ariel Martinez-Chavez, Larry E Wagner, Sundeep Malik, Tyler Allison, Briar Bell, Alexander B Seryshev, Julio Cordero-Morales, Matthew L Baker, David I Yule, Irina I Serysheva.

Calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs) is a fundamental signaling mechanism that regulates diverse cellular processes. Among the three mammalian IP3R isoforms, IP3R2 is widely expressed, yet its structural basis for activation and regulation remains unclear. Here, we report cryo-EM structures of mammalian IP3R2 in ligand-free (closed) and Ca2+/IP3/ATP-bound (activated) states at 3.3 Å and 3.6 Å resolution, respectively. These structures define the architecture of IP3R2 and reveal conformational transitions associated with channel activation. Although the IP3-binding pocket is conserved, subtype-specific differences in IP3 affinity likely arise from conformational dynamics of the regulatory ARM2 domain. Comparative analyses of IP3R isoforms identify subtype-specific allosteric networks and domain motions that underlie differential regulation. We further define the ATP-binding site and, through mutagenesis and electrophysiology, establish the structural basis for ATP modulation of channel activity. Together, these findings reveal mechanisms of IP3R2 activation and subtype-specific regulation, providing a framework for understanding isoform-dependent Ca2+ signaling.

DOI: https://doi.org/10.1038/s41467-026-75806-y
Mol Metab. 2026 Aug 25. pii: S2212-8778(26)00117-1. [Epub ahead of print] 102433

Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.

Essam A Assali, Mahmoud Taha, Ahmad Salhab, Johnny Amer, Karthickeyan Chella Krishnan, Marko Kostic, Michaela Veliova, Alexandra J Brownstein, Orian S Shirihai, Rifaat Safadi, Israel Sekler.

  Mitochondrial calcium signaling, particularly its glucagon-mediated oscillatory dynamics, plays a pivotal role in regulating hepatic metabolism and is known to be disrupted in steatotic liver disease. We recently identified the mitochondrial Na+/Ca2+ exchanger NCLX as a key mediator of glucagon-induced mitochondrial calcium oscillations, essential for proper gluconeogenic function. Here, using hepatocyte-specific NCLX knockout (cKO) mice, we demonstrate that NCLX is critical for intrahepatic lipolysis and fatty acid oxidation (FAO); its loss impairs glucagon-stimulated lipid droplet catabolism and blunts FAO. Mechanistically, we find that NCLX deficiency disrupts allosteric activation of lipolytic enzymes and increases CPT1 sensitivity to malonyl-CoA-mediated inhibition, resulting in defective lipolysis and FAO. We further show that glucagon regulates hepatic NCLX via cAMP/PKA-dependent phosphorylation at NCLX Ser258. Notably, PDE2A acts as a negative regulator of this pathway by degrading mitochondrial cAMP. Hepatic mitochondrial PDE2A abundance and cAMP-degrading activity are elevated in HFD, and in vivo BAY 60-7550 treatment suppresses mitochondrial cAMP degradation and augments PKA signaling in steatosic livers. Pharmacologic inhibition of PDE2A with BAY 60-7550 enhances NCLX phosphorylation, restores mitochondrial calcium efflux and oscillations, and stimulates FAO in an NCLX-dependent manner. Importantly, we uncover that cAMP/PKA-dependent phosphorylation of NCLX at Ser258 is suppressed in human steatotic livers, and that pharmacologic inhibition of PDE2A ameliorates hepatic FAO and steatosis in both dietary and genetic MASLD models. Collectively, our findings establish the glucagon-PKA-PDE2A-NCLX signaling axis as a key metabolic rheostat integrating mitochondrial calcium dynamics with lipid homeostasis, providing a promising therapeutic target for MASLD.

Keywords:  Glucagon signaling; Hepatic steatosis; MASLD (Metabolic dysfunction-associated steatotic liver disease); NCLX; PDE2A (Phosphodiesterase 2A); fatty acid oxidation; lipolysis; mitochondrial bioenergetics; mitochondrial calcium signaling

DOI:  https://doi.org/10.1016/j.molmet.2026.102433
Nat Aging. 2026 Aug 25.

cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.

John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova.

Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.

DOI: https://doi.org/10.1038/s43587-026-01206-y
Trends Endocrinol Metab. 2026 Aug 26. pii: S1043-2760(26)00176-1. [Epub ahead of print]

Mitochondria as central regulators of cancer progression and antitumor immunity.

Aurora Gomez-Duran, Inmaculada Martínez-Reyes.

  Mitochondria coordinate metabolic and signaling pathways that influence cancer progression across multiple stages of the disease. Beyond supporting tumor growth, mitochondria contribute to metastatic dissemination and shape interactions between tumor and immune cells through diverse outputs, including metabolite production, redox regulation, and mitochondrial genome dynamics. In this review, we discuss how mitochondrial functions sustain cancer cell proliferation, regulate pathways that facilitate metastatic progression, and influence antitumor immunity. We further highlight emerging roles for mitochondrial DNA variation, intercellular mitochondrial transfer, and mitochondrial dysfunction in immune cell exhaustion and senescence. Finally, we discuss how these advances are revealing therapeutic opportunities to target mitochondrial pathways and enhance the efficacy of current cancer immunotherapies.

Keywords:  antitumor immunity; cancer metabolism; metastasis; mitochondria; mitochondrial genetics

DOI:  https://doi.org/10.1016/j.tem.2026.07.005
J Biomed Sci. 2026 Aug 27. pii: 86. [Epub ahead of print]33(1):

Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.

Jing-Yiing Wu, Tzu-Ching Chang, Mei-Jen Chen, Shih-Han Cho, Jun-Yang Liou, Cheng-Chin Kuo, Kenneth K Wu.

   BACKGROUND: Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.
METHODS: We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.
RESULTS: The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH/succinate.
CONCLUSIONS: These findings indicate that the mitochondrial fragmentation-SDH-succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.

Keywords:  Cancer metabolism; Dynamin-related protein 1; Hepatocellular carcinoma; Mitochondrial dynamics; Succinate; Succinate dehydrogenase

DOI:  https://doi.org/10.1186/s12929-026-01289-0
Wound Repair Regen. 2026 Jul-Aug;34(4):34(4): e70203

Cellular Senescence in Skin Wound Repair: Dual Roles and Senotherapeutic Interventions.

J A Santiago-de-la-Cruz, L J García-Flores, R N Alonso-Cruz, N A Rivero-Segura, A Cabrera-Wrooman.

  Skin wound repair is a complex process involving numerous signalling pathways in various cell types. Cellular senescence (CS), described as a proliferative limit, has dual implications in this process. In acute wounds, transient cellular senescence acts as a beneficial mechanism that facilitates tissue repair through the controlled secretion of the senescence-associated secretory phenotype (SASP), promoting immune cell recruitment, myofibroblast differentiation and angiogenesis. In contrast, chronic wound settings, which are frequently associated with pathological conditions including type 2 diabetes, persistent hypoxia and advanced age, promote the buildup of senescent cells and impair their immune-mediated elimination. This generates a cycle of chronic inflammation through sustained SASP secretion, resulting in altered keratinocyte migration, dysfunctional fibroblast activity, abnormal extracellular matrix remodelling and healing failure. The therapeutic landscape targeting CS is rapidly evolving: senolytic approaches demonstrate efficacy in eliminating senescent cells, while senomorphic strategies effectively modulate the SASP without eliminating senescent cells. This review summarises the multifaceted involvement of CS in the healing cascade, focusing on molecular mechanisms and current senotherapeutic evidence. This analysis is crucial for developing targeted therapies that preserve the beneficial functions of CS while counteracting its pathological effects in chronic wounds and age-related tissue dysfunction.

Keywords:  SASP and wounds; cellular senescence; senotherapeutics; wound healing

DOI:  https://doi.org/10.1111/wrr.70203