bims-cesemi 2026-10-18 papers

Issue of 2026–10–18
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Dev Cell. 2026 Oct 14. pii: S1534-5807(26)00358-8. [Epub ahead of print]61(10): 1945-1946

Mitochondria strike two hits to drive the SASP.

Senescent cells develop a persistent inflammatory signature with broad consequences for tissue function and disease. Martini et al.1 show that mitochondrial citrate metabolism drives inflammation through a pathway that acts independently of mitochondrial DNA-driven immune signaling yet cooperates with it to amplify the inflammatory response.

DOI: https://doi.org/10.1016/j.devcel.2026.09.010

Cells. 2026 Sep 28. pii: 1766. [Epub ahead of print]15(19):

TRPs-NCX2 Axis Jointly Preserves Pancreatic Beta Cell Susceptibility/Sensitivity to Elevated Glucose.

Adlet Sagintayev, Furkan E Oflaz, Andra Kanlinuro, Savina van Amsterdam, Benjamin Gottschalk, Rene Rost, Zhanat Koshenov, Roland Malli, Wolfgang F Graier.

Background: For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca2+ leak via phosphorylated presenilin-1 (PS1). In the current work, we investigated how cells maintain the ER Ca2+ content during this continuous Ca2+ leak. Methods: Ca2+ imaging for ER, cytosolic and subplasmalemmal Ca2+, high resolution respirometry, and ELISA for insulin secretion were used. Results: A novel ER Ca2+ refilling mechanism driven by reverse-mode NCX2, which is fueled by local Na+ influxes through TRPC3 and TRPV4 channels that are independent of STIM-ORAI1 was found in pancreatic rodent and human beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca2+ levels, abolishes glucose-induced cytosolic Ca2+ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. Conclusions: We identified a novel, ORAI1-independent "TRPs-NCX2" relay that couples Na+ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca2+ stores during physiological basal ER Ca2+ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.

Keywords: ER Ca2+ leak; ER Ca2+ refilling; NCX; TRPC3; TRPV4; beta cell; glucose-stimulated insulin secretion

DOI: https://doi.org/10.3390/cells15191766

Front Immunol. 2026 ;17 1998525

Editorial: Implications of senescence in cancer immunology.

Alessandra Zingoni, Gordon Cook, Laura Senovilla.

Keywords: cancer immunology; senescence; senescence-associated secretory phenotype; senescent tumor microenvironment; therapy-induced senescence

DOI: https://doi.org/10.3389/fimmu.2026.1998525

Pharmacol Rep. 2026 Oct 14.

GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.

Juan De Los Santos-Jiménez, José A Campos-Sandoval, Jessica Sudderth, Lauren G Zacharias, João Santos Patricio, Francisco J Alonso, Javier Márquez, Thomas P Mathews, Ralph J DeBerardinis, José M Matés.

BACKGROUND: Glioblastoma (GBM) exhibits extensive metabolic reprogramming, including glucose and glutamine (Gln) addiction, with Gln being converted into glutamate by glutaminase, encoded by the GLS and GLS2 genes. GLS2 acts as a context-dependent tumor suppressor, although the underlying mechanisms remain poorly understood. GLS2 is silenced in GBM, and we previously showed that its re-expression modulates pyruvate dehydrogenase (PDH) activity and tricarboxylic acid cycle (TCAC) metabolism, suggesting a distinct metabolic rewiring associated with its tumor-suppressive function.
METHODS: LN229 and T98G GBM cell lines were used as experimental models. Metabolomic profiling by liquid chromatography-mass spectrometry was performed to compare changes in central metabolic pathways following GLS2 or GLS overexpression. Glutaminase and PDH enzymatic activities were measured, and Western blotting was performed to assess GLS, GLS2, and PDHA1 protein levels and PDHA1 phosphorylation. A Seahorse analyzer was employed to quantify real-time ATP production derived from glycolysis and oxidative phosphorylation.
RESULTS: Overexpression of GLS2, but not GLS, in LN229 cells caused the accumulation of TCAC-related metabolites, except for citrate, whose depletion is attributed to GLS2's effect on PDH phosphorylation, causing reduced PDH activity. This was accompanied by decreased levels of several acyl-carnitines. Furthermore, GLS2 induced the accumulation of glucose/fructose, while reducing levels of glucose-6-phosphate and pentose-phosphates, consistent with altered glycolysis. GLS2 also diminished the ATP/AMP ratio, confirmed by a reduced ATP synthesis rate, particularly glycolytic ATP, whereas mitochondrial ATP production remained unaltered.
CONCLUSIONS: GLS2 exerts an isoenzyme-specific effect on Gln and glucose metabolism in GBM, likely modulating the glycolysis/pentose-phosphate pathway (PPP)-TCAC-axis.

Keywords: Cancer metabolism; GLS2; Glioblastoma; Glutaminase; Glutamine; Pyruvate dehydrogenase

DOI: https://doi.org/10.1007/s43440-026-00908-9

J Mol Biol. 2026 Oct 12. pii: S0022-2836(26)00437-7. [Epub ahead of print] 170064

Lactate-associated H3K18 lactylation and SYT8 in the temozolomide response of glioblastoma cells.

Sansong Chen, Yiming Deng, Limin Cheng.

Lactate and histone H3K18 lactylation (H3K18la) have been linked to glioblastoma biology. We examined their relationship with synaptotagmin 8 (SYT8) and the response to temozolomide (TMZ). U251MG and U87MG cells were cultured under normoxia or hypoxia and exposed to TMZ, sodium lactate or both. H3K18la enrichment at the SYT8 promoter was assessed by chromatin immunoprecipitation. The effects of SYT8 knockdown were evaluated using CCK-8, colony formation, flow cytometry, wound healing and Transwell assays. Lactate and protein abundance were measured, including H3K18la normalized to total H3 in the four-group experiment. Endpoint tumor weight was assessed in a subcutaneous U87MG xenograft model. TMZ reduced CCK-8 signal and intracellular lactate in both cell lines, whereas lactate supplementation attenuated several effects of TMZ. H3K18la was enriched at the SYT8 promoter, and SYT8 knockdown was accompanied by lower lactate and H3K18la signals. Under TMZ treatment, SYT8-depleted cells formed fewer colonies and had a higher apoptosis fraction. Lactate partly reversed these changes and increased H3K18la/total H3 while SYT8 protein remained low. The combined SYT8-knockdown and TMZ group had the lowest endpoint tumor weight. These results link SYT8 to lactate-associated H3K18 lactylation and TMZ response in GBM cells. The reciprocal changes in SYT8, lactate and H3K18la suggest a possible feedback relationship that warrants further mechanistic study.

Keywords: Glioblastoma; Histonelactylation; Hypoxia; SYT8; Temozolomide response

DOI: https://doi.org/10.1016/j.jmb.2026.170064

J Bioenerg Biomembr. 2026 Oct 15. pii: 58. [Epub ahead of print]58(1):

Mitofusin 2 orchestrates mitochondrial metabolic homeostasis and suppresses cutaneous squamous cell carcinoma by stabilizing ER-mitochondria contacts.

Xianpeng Ma, Jing Liu, Xiao Shao, Yupeng Huang, Guangyao Hu.

This study aimed to elucidate the biological role of Mitofusin 2 (Mfn2) in cutaneous squamous cell carcinoma (cSCC) and evaluate how its regulation of mitochondria-associated membranes (MAMs) may suppress tumor progression by reshaping mitochondrial metabolic homeostasis and apoptosis. We compared Mfn2 expression between normal keratinocytes (HaCaT) and cSCC cells (A431), establishing a stable Mfn2-overexpressing (Mfn2-OE) A431 model. Structural impacts on ER-mitochondrial contacts and MAMs were evaluated using immunofluorescence, STED super-resolution microscopy, TEM, and subcellular fractionation (VDAC1/IP3R/Grp75). Functional assays assessed ER-mitochondrial calcium transport (probes), lipid peroxidation/ROS (C11-BODIPY/DCFH-DA), mitochondrial membrane potential, and ATP levels (JC-1/ATP assays). Mitochondria-dependent apoptosis (Bcl-2/p53/Cytochrome c/Caspase-3) was analyzed via flow cytometry, TUNEL, and Western blot. Phenotypes were assessed using CCK-8, EdU, colony formation, and Transwell assays. In vivo xenografts in nude mice were monitored, with H&E/IHC analysis. Proteomics and untargeted metabolomics (LC-MS) were performed (n = 6/group). Mfn2 protein levels were lower in A431 cSCC cells than in HaCaT keratinocytes. Mfn2-OE enhanced ER-mitochondrial contacts, increased MAMs, and stabilized the VDAC1-Grp75-IP3R complex. This enhanced calcium transport, reduced ROS/lipid peroxidation, stabilized MMP, and decreased ATP. Mfn2-OE inhibited Bcl-2, promoted p53 mitochondrial translocation and Cytochrome c release, activating Caspase cascades. Both in vitro and in vivo, Mfn2-OE suppressed proliferation, invasion, and tumor growth. Proteomics/metabolomics revealed metabolic reprogramming involving energy metabolism, lipid metabolism, and redox balance. Mfn2 may act as a tumor-suppressive regulator in the A431 cSCC model by stabilizing MAMs, remodeling mitochondrial metabolic homeostasis, and activating mitochondria-dependent apoptosis.

Keywords: Cutaneous squamous cell carcinoma; Mitochondria-associated membranes; Mitochondrial metabolism; Mitofusin 2; Tumor suppression

DOI: https://doi.org/10.1007/s10863-026-10132-y