bims-miptne 2025-03-09 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–03–09
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Platelets and mitochondria: the calcium connection.
Cyclophilin D (CypD) ablation prevents neurodegenerative and cognitive damage induced by caspase-3 cleaved tau.
Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer.
Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice.
Resistance to PD-1/PD-L1 immune checkpoint blockade in advanced non-small cell lung cancer.
Calcium release via IP3R/RyR channels contributes to the nuclear and mitochondrial Ca2+ signals elicited by neuronal stimulation.
iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.
Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
Enhancing immunotherapy with tumour-responsive nanomaterials.

Mol Biol Rep. 2025 Mar 03. 52(1): 276

Platelets and mitochondria: the calcium connection.

Durre Shehwar, Saima Barki, Alessandro Aliotta, Debora Bertaggia Calderara, Lucas Veuthey, Cindy Pereira Portela, Lorenzo Alberio, Muhammad Rizwan Alam.

  Calcium signaling has a fundamental importance in maintaining various platelet functions, such as those involved in hemostasis and thrombosis. Agonist-induced mobilization of calcium (Ca2+) from intracellular stores coupled with activation of store-operated calcium entry (SOCE) and non-SOCE or receptor-operated calcium entry (ROCE) regulates platelet degranulation, integrin activation, shape change, generation of thromboxane A2, and aggregation or procoagulant function. Platelet mitochondria also take up a small amount of cytosolic Ca2+ that contributes to bioenergetics, cytosolic Ca2+ buffering, cell signaling and death. Voltage-dependent anion channels (VDAC) in the outer mitochondrial membrane and mitochondrial Ca2+ uniporter complex (MCUC) in the inner mitochondrial membrane (IMM) are pivotal for transporting Ca2+ into the mitochondrial matrix. On the other hand, matrix Ca2+ efflux is dependent on the IMM localized sodium/calcium exchanger (NCLX). Despite the well-established role of cytosolic Ca2+, the participation of mitochondrial Ca2+ homeostasis in platelet physiology remains unknown. This mini-review summarizes the recent developments in the field of mitochondrial Ca2+ transport in platelet physiology.

Keywords:  Apoptotic platelets; Mitochondrial calcium; Platelet activation; Procoagulant platelets

DOI:  https://doi.org/10.1007/s11033-025-10389-3
Free Radic Biol Med. 2025 Feb 27. pii: S0891-5849(25)00118-2. [Epub ahead of print]

Cyclophilin D (CypD) ablation prevents neurodegenerative and cognitive damage induced by caspase-3 cleaved tau.

Margrethe A Olesen, Francisca Villavicencio-Tejo, Gail V W Johnson, George A Porter, Rodrigo A Quintanilla.

  Abnormal tau modifications are one of the main contributors to neurodegenerative processes present during Alzheimer´s disease (AD). In this context, truncated tau by caspase-3, a pathological tau form, affects mitochondrial function and antioxidant regulation, contributing to synaptic and cognitive impairment in AD mouse models. We previously showed that the presence of caspase-3 cleaved tau promotes mitochondrial impairment in neuronal cells, where Cyclophilin-D (CypD) protein could be a crucial element. CypD is considered the master regulator of mitochondrial permeability transition pore (mPTP) opening, and its ablation prevents neurodegenerative and cognitive damage induced by β-amyloid in mouse models of AD. However, the possible role of CypD in the neurodegenerative processes mediated by caspase-3-cleaved tau has not been explored. Here, we use tau (-/-) and CypD (-/-) knock-out mice that were subjected to right-side hippocampal stereotaxic injection to induce GFP (AAV-Syn-GFP), full-length (AAV-Syn-GFP-T4) or caspase-3-cleaved (AAV-Syn-GFP-T4C3) tau expression. Then, cognitive performance, synaptic architecture, and hippocampal mitochondrial function were evaluated two months later. We observed that caspase-3 cleaved tau expression inducing cognitive decline, vesicle and synaptic protein deregulation, and mitochondrial impairment generated by the mPTP opening. More interestingly, when caspase-3 cleaved tau was expressed in the hippocampus of CypD (-/-) mice, cognitive decline, synaptic impairment, and mitochondrial damage mediated by mPTP were prevented, demonstrating a novel role of CypD in neurodegenerative changes induced by truncated tau in AD.

Keywords:  Alzheimer disease; Caspase-3 cleaved tau; Cognitive impairment; Cyclophilin-D (CypD); Mitochondrial dysfunction; mPTP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.035
Front Immunol. 2025 ;16 1486329

Analysis of tumor-infiltrating exhausted T cells highlights IL-6 and PD1 blockade as a combined immunotherapy strategy for non-small cell lung cancer.

Lulu Zhang, Xiyuan Guo, Xiaoke Sun, Jue Liao, Qin Liu, Yingchun Ye, Zhihui Yang, Ratchada Cressey, Qing He, Qing Yuan.

   Objective: Given the limitations of immunotherapy for treating non-small cell lung cancer (NSCLC), we investigated the phenotype and function of exhausted CD8+T cells and analyzed a novel combination immunotherapy to restore the effector killing function of tumor-infiltrating CD8+T lymphocyte (TIL).
Methods: We examined the expression and function of immunosuppressive molecules on CD8+T cells of peripheral blood mononuclear cells (PBMCs) and TILs by using prospectively collected peripheral blood, pleural effusions, and tumor tissues from patients with NSCLC and correlated the results with clinical data. We then evaluated the effect of interleukin 6 (IL-6) stimulation on CD8+T cells. Finally, we assessed the effects of combined blockade of PD1 and IL-6 on macrophage recruitment in a zebrafish macrophage model and CD8+ T cell function and tumor growth in PBMC humanized mouse model.
Results: The expression of exhaustion markers on CD8+ T cells was found to be notably higher in both tumor and paraneoplastic tissues compared to peripheral blood. Furthermore, the degree of CD8+ T cell exhaustion exhibited a progressive increase with proximity to the tumor. When CD8+ T cells from peripheral blood and tumor tissues of NSCLC patients were stimulated with IL-6, the expression level of exhaustion markers, especially PD1, was further elevated. In the in vitro experiment, the combined inhibition of IL-6 and PD1 substantially enhanced the effector killing function of CD8+ T cells in NSCLC pleural effusion samples. In a macrophage-labeled zebrafish model, combined blockade of IL-6 and PD1 enhanced the recruitment of macrophages. In PBMC humanized mouse model, combined blockade of IL-6 and PD1 enhanced the inhibition of tumor growth.
Conclusion: Our data suggest that CD8+ T cells in NSCLC patients were in a state of exhaustion and combined blockade of IL-6 and PD1 to restore CD8+ T cell function to inhibit tumor growth may be an effective clinical strategy for the treatment of NSCLC.

Keywords:  PD1; combined blockade; exhausted CD8+T cells; interleukin-6; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1486329
ACS Cent Sci. 2025 Feb 26. 11(2): 228-238

Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice.

Michael P Mulligan, Matthew W Boudreau, Brooke A Bouwens, Yoongyeong Lee, Hunter W Carrell, Junyao Zhu, Spyro Mousses, David J Shapiro, Erik R Nelson, Timothy M Fan, Paul J Hergenrother.

Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5-10 years of treatment with adjuvant endocrine therapy. This prolonged intervention is associated with a host of undesired side effects that reduce patient compliance, and ultimately therapeutic resistance and disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent and refractory disease with minimal dosing; however, there is little precedent for marked tumor regression with a single dose of a small molecule therapeutic. Herein we report ErSO-TFPy as a small molecule that induces quantitative or near-quantitative regression of tumors in multiple mouse models of breast cancer with a single dose. Importantly, this effect is robust and independent of tumor size with eradication of even very large tumors (500-1500 mm3) observed. Mechanistically, these tumor regressions are a consequence of rapid induction of necrotic cell death in the tumor and are immune cell independent. If successfully translated to human cancer patients, the benefits of such an anticancer drug that is effective with a single dose would be significant.

DOI: https://doi.org/10.1021/acscentsci.4c01628
Crit Rev Oncol Hematol. 2025 Feb 28. pii: S1040-8428(25)00071-X. [Epub ahead of print]209 104683

Resistance to PD-1/PD-L1 immune checkpoint blockade in advanced non-small cell lung cancer.

Lijun Li, Haihong Pu, Xiaoxin Zhang, Xiaotian Guo, Guangrui Li, Minghui Zhang.

  Lung cancer is one of the most common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for about 85 %. Although immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have significantly improved the prognosis of patients with NSCLC. There are still many patients do not benefit from ICIs. Primary resistance remains a major challenge in advanced NSCLC. The cancer-immunity cycle describes the process from antigen release to T cell recognition and killing of the tumor, which provides a framework for understanding anti-tumor immunity. The classical cycle consists of seven steps, and alterations at each stage can result in resistance. This review examines the current status of PD-1/PD-L1 blockade in the treatment of advanced NSCLC and explores potential mechanisms of resistance. We summarize the latest clinical trials of PD-1/PD-L1 inhibitors combined with other therapies and explore potential targets for overcoming primary resistance to PD-1/PD-L1 inhibitors.

Keywords:  Drug resistance; Non-small cell lung cancer; PD-1/PD-L1 inhibitors

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104683
Biochem Biophys Res Commun. 2025 Feb 09. pii: S0006-291X(25)00159-7. [Epub ahead of print]754 151445

Calcium release via IP3R/RyR channels contributes to the nuclear and mitochondrial Ca2+ signals elicited by neuronal stimulation.

Silvia Gleitze, Omar A Ramírez, Ignacio Vega-Vásquez, Emely Stefan, C Peter Bengtson, Andrea Paula-Lima, Hilmar Bading, Cecilia Hidalgo.

  The brain constantly adapts to environmental changes by modifying the expression of genes that enable synaptic plasticity, learning and memory. The expression of several of these genes requires nuclear calcium (Ca2+) signals, which in turn requires that Ca2+ signals generated by neuronal activity at the synapses or the soma propagate to the nucleus. Since cytoplasmic Ca2+ diffusion is highly restricted, Ca2+ signal propagation to the nucleus requires the participation of other cellular mechanisms. The inositol trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) channels, both of which reside in the endoplasmic reticulum (ER) membrane, play key roles in cellular Ca2+ signal generation. Yet, their roles in the generation of nuclear and mitochondrial Ca2+ signals induced by neuronal activity require further investigation. Here, the impact of IP3R1 or RyR2 knockdown on gabazine-induced nuclear and mitochondrial Ca2+ signals in neurons was evaluated. To this aim, recombinant adeno-associated viruses (rAAVs) were used to introduce small hairpin RNAs (shRNAs) to knockdown type-1 (IP3R1) and type-2 (RyR2) channel expression in cultured rat hippocampal neurons. Additionally, synaptic contact numbers were assessed through immunocytochemistry. Knockdown of IP3R1 or RyR2 channels significantly reduced their protein contents and the generation of gabazine-induced nuclear and mitochondrial Ca2+ signals, without altering synaptic contact numbers. Our results highlight the contribution of IP3R1 and RyR2 channels to the generation of nuclear and mitochondrial Ca2+ signal induced by neuronal activity, reinforcing the role that these Ca2+ release channels play in hippocampal synaptic plasticity and memory formation.

Keywords:  Gabazine; Hippocampal neurons; IP(3)R1/RyR2 channel knockdown; Nuclear and mitochondrial calcium levels; Synaptic contacts

DOI:  https://doi.org/10.1016/j.bbrc.2025.151445
Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00146-9. [Epub ahead of print]44(3): 115375

iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.

Binxian Wang, Chao Huang, Xuan Liu, Zhenni Liu, Yilei Zhang, Wei Zhao, Qiuran Xu, Ping-Chih Ho, Zhengtao Xiao.

  Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.

Keywords:  CP: Cancer; CP: Metabolism; hepatocellular carcinoma; information propagation; metabolic enzyme activity; tumor stratification; tumor-immune microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115375
EMBO J. 2025 Feb 28.

Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.

Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji.

  Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.

Keywords:  Bioenergetics; Pyrimidine Nucleotides; SLC25; Thermogenesis; Uncoupling Protein

DOI:  https://doi.org/10.1038/s44318-025-00395-3
Nat Rev Clin Oncol. 2025 Mar 06.

Enhancing immunotherapy with tumour-responsive nanomaterials.

Stephen W Linderman, Louis DeRidder, Lucía Sanjurjo, Michael B Foote, María José Alonso, Ameya R Kirtane, Robert Langer, Giovanni Traverso.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes.

DOI: https://doi.org/10.1038/s41571-025-01000-6