bims-cesemi 2025-08-17 papers

Issue of 2025–08–17
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Science. 2025 Aug 14. 389(6761): 685-686

Mitochondria hoard folate to starve a parasite.

Anu Suomalainen, Joni Nikkanen.

Metabolic immunity contributes to cells' defenses against Toxoplasma gondii.

DOI: https://doi.org/10.1126/science.aea0875

Free Radic Res. 2025 Aug 14. 1-20

Mitochondria and redox homeostasis - the backseat drivers in glioma.

Shruti Patrick, Ellora Sen.

Mitochondrial function and redox regulatory processes are crucial aspects of cellular metabolism and energy production. Cancers, including gliomas, largely exhibit altered mitochondrial function, which can lead to changes in cellular signaling pathways and redox homeostasis. Aberrant redox signaling can promote glioma progression by influencing cell proliferation, metastasis and therapeutic response. Several cancer-associated driver mutations - genetic alterations that confer survival and growth advantage to cancer cells, are associated with gliomas and affect mitochondrial function and redox states. Here is an overview of the crucial intersection between mitochondrial function and driver genes in glioma, highlighting some of the recent advances that augment our understanding of this intersection.

Keywords: Cancer drivers; Driver mutations; Glioma; Mitochondria; Redox homeostasis

DOI: https://doi.org/10.1080/10715762.2025.2548479

Front Syst Biol. 2024 ;4 1343006

Calcium oscillations in HEK293 cells lacking SOCE suggest the existence of a balanced regulation of IP3 production and degradation.

Clara Octors, Ryan E Yoast, Scott M Emrich, Mohamed Trebak, James Sneyd.

The concentration of free cytosolic Ca2+ is a critical second messenger in almost every cell type, with the signal often being carried by the period of oscillations, or spikes, in the cytosolic Ca2+ concentration. We have previously studied how Ca2+ influx across the plasma membrane affects the period and shape of Ca2+ oscillations in HEK293 cells. However, our theoretical work was unable to explain how the shape of Ca2+ oscillations could change qualitatively, from thin spikes to broad oscillations, during the course of a single time series. Such qualitative changes in oscillation shape are a common feature of HEK293 cells in which STIM1 and 2 have been knocked out. Here, we present an extended version of our earlier model that suggests that such time-dependent qualitative changes in oscillation shape might be the result of balanced positive and negative feedback from Ca2+ to the production and degradation of inositol trisphosphate.

Keywords: HEK293 cells; IP3; PLC regulation; SOCE; STIM; bifurcation analysis; calcium influx; calcium oscillation

DOI: https://doi.org/10.3389/fsysb.2024.1343006

J Biol Chem. 2025 Aug 12. pii: S0021-9258(25)02440-8. [Epub ahead of print] 110589

Inositol (1,4,5)-trisphosphate 5-phosphatase promotes survival of uveal melanoma by regulating oncogenic G protein-driven calcium oscillations.

Michael D Onken, Carol M Makepeace, Kevin M Kaltenbronn, McKenzie Demourelle-Washington, Kisha D Piggott, Dennis Goldfarb, David J Kast, Silvia Jansen, Kendall J Blumer.

Mutant constitutively active (CA) G protein α-subunits encoded by GNAQ or GNA11 (CA-GNAQ/11) drive uveal melanoma (UM), occur in uncommon subtypes of other cancers, and cause Sturge-Weber syndrome and other capillary malformations. CA-GNAQ/11 activates phospholipase Cβ, which cleaves phosphatidylinositol (4,5)-bisphosphate at high rate to produce diacylglycerol that drives oncogenesis and inositol (1,4,5)-trisphosphate (IP3) that releases Ca2+ from intracellular stores and triggers store-operated Ca2+ entry. For poorly understood reasons, high IP3 flux in UM cells does not elicit Ca2+ overload and death. To address this question, we studied INPP5A, a farnesylated, membrane-bound inositol polyphosphate 5-phosphatase that degrades IP3. We show that INPP5A is upregulated in and required by CA-GNAQ/11-driven UM cell lines and is genetically preserved in UM tumors. We found that INPP5A is reversibly palmitoylated, which together with farnesylation targets the enzyme to subcellular compartments and regulates Ca2+ mobilization. Although CA-GNAQ/11 is constitutively active, we discovered that it drives low-frequency Ca2+ oscillations in UM cells. We found that acute inhibition of INPP5A in UM cells augments Ca2+ oscillation rate, a diagnostic effect of elevating IP3 levels. These results indicated that INPP5A safeguards CA-GNAQ/11-driven UM tumors against Ca2+ overload and death by regulating IP3-evoked Ca2+ oscillations. As universal frequency-encoded signals, Ca2+ oscillations likely regulate vital functions in UM cells. Our findings suggest strategies for targeting INPP5A in diseases or disorders driven by CA-GNAQ/11.

DOI: https://doi.org/10.1016/j.jbc.2025.110589

Nat Commun. 2025 Aug 14. 16(1): 7540

Boosting energy metabolism and biosynthesis in diverse organisms by a common bacterial salvage lipoylation protein.

Runqing Yang, Yingying Wang, Minghua Kong, Zhijuan Hu, Zhe Zhang, Kun Shen, Jiali Meng, An-Ping Zeng.

Lipoylation is a highly conserved post-translational modification (PTM) crucial for energy metabolism enzymes, with distinct pathways across organisms. Whereas bacteria like Escherichia coli inherit both salvage and de novo pathways, only the latter is found in eukaryotes. Here, we present a PTM-based strategy that achieves multiple metabolic benefits with a single intervention. By expressing E. coli-derived lipoate protein ligase A (LplA) from the salvage pathway, we enhance lipoylation and the activities of the pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase complexes and glycine cleavage system in mammalian, algal and fungal cells, leading to improved energy metabolism, cofactor supply, mitochondrial function, and overall cell physiology. Our approach specifically targets multiple metabolic hubs through PTM modulation. Beyond its fundamental significance, our finding presents a unified and efficient way to boost biosynthesis across organisms, demonstrated in antibody production in Chinese hamster ovary cells, fatty acids synthesis in cyanobacteria and diatoms, and organic acid production in fungi.

DOI: https://doi.org/10.1038/s41467-025-62638-5

Nature. 2024 May;629(8012): 518-520

How to kill the 'zombie' cells that make you age.

Carissa Wong.

Keywords: Ageing; Drug discovery; Gene therapy; Immunology

DOI: https://doi.org/10.1038/d41586-024-01370-4

Mol Cancer Ther. 2025 Aug 14.

Co-Targeting Bcl-xL with Mcl-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.

R Taylor Ripley, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen.

Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging non-canonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its anti-apoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2 targeted therapy to undermine therapeutic resistance in patients with DM.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0873

Adv Sci (Weinh). 2025 Aug 13. e07248

Senescence-Inducing Therapy Sequential NIR-II Mild Photothermal/Senolytic Therapy of Triple Negative Breast Cancer.

Liya Yu, Yehui Kang, Mengdie Yu, Yuejia Ding, Yang Chen, Qingyuan Wu, Yu Cai, Huiyu Liu, Zhenye Lv.

Targeting the limited therapeutic options and frequent drug resistance in triple negative breast cancer (TNBC) remains a critical clinical challenge. Here, a novel sequential theranostic mild strategy leveraging cellular senescence to enhance mild photothermal therapy (PTT) and promote TNBC eradication is presented. Palbociclib, a clinically-approved CDK4/6 inhibitor, is used to induce senescence in a murine TNBC model, resulting in both tumor growth arrest and increased heat sensitivity due to HSP70 downregulation. Capitalizing on this vulnerability, an NIR-II theranostic nanoplatform (IQ NPs) composed of the photothermal agent IR1061 and the senolytic quercetin (Qu), fabricated via nanoprecipitation is developed. IQ NPs demonstrated enhanced mild PTT efficacy, further potentiated by Qu-mediated HSP70 suppression and augmented senolysis. This findings highlight the potential of exploiting senescence-inducing vulnerabilities to amplify mild PTT efficacy, providing a promising new therapeutic avenue for this aggressive and recalcitrant malignancy.

Keywords: CDK4/6 inhibitor; mild PTT; senescence‐inducing therapy; senolytics; triple negative breast cancer

DOI: https://doi.org/10.1002/advs.202507248