bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–05–25
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. MCU regulating bone remodeling and osteogenic function through mitochondrial calcium homeostasis and oxidative stress alteration.
  2. Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer.
  3. Embracing cancer immunotherapy with manganese particles.
  4. Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site.
  5. Integrating optical neuroscience tools into touchscreen operant systems.
  6. SMAC/DIABLO: A Guardian Angel in Boosting Anticancer Drug-Induced Apoptosis.
  1. Free Radic Biol Med. 2025 May 17. pii: S0891-5849(25)00276-X. [Epub ahead of print]236 87-97
    MCU regulating bone remodeling and osteogenic function through mitochondrial calcium homeostasis and oxidative stress alteration.
    Chen Li, Jiyu Sun, Huiling Ling, Ziqi Qin, Xiting Zhu, Xinliang Fu, Tao Li, Xueqi Gan.
      Mitochondria regulate cellular metabolism, signaling, immunity, and differentiation, affecting various diseases including diabetes, cancer, and osteoporosis. Mitochondrial calcium uniporter (MCU) unidirectionally transports Ca2+ across the inner mitochondrial membrane to the mitochondrial matrix. Ca2+ shuttles continuously through mitochondria and plays an essential role in the regulation of several cellular processes. However, the effects of MCU on bone metabolism-related diseases and the underlying pathophysiologic mechanisms have not been fully elucidated. Here, we found that MCU overexpression led to reduced bone volume fraction, bone trabecular thickness and number in mice in vivo. That was associated with MCU-mediated oxidative stress, overload of mitochondrial calcium, and decrease in mitochondrial membrane potential in osteoblasts. In vitro, MCU activation inhibited osteogenic differentiation capacity of osteoblasts in both early and late stages of osteogenesis. Additionally, MCU opening negatively regulated BMP/Smad signaling through ROS accumulation, thereby inhibiting osteogenic differentiation. Our results provide promising new targets for the future development of osteogenic function regulation and tissue engineering applications.
    Keywords:  BMP/Smad; Calcium homeostasis; Mitochondria; Mitochondrial calcium uniporter; Osteogenesis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.001
  2. Front Immunol. 2025 ;16 1554871
    Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer.
    Jiacheng Zhang, Zehao Song, Yuanjie Zhang, Chentong Zhang, Qi Xue, Guochao Zhang, Fengwei Tan.
      Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.
    Keywords:  NSCLC; biomarker; circulating biomarkers; immune checkpoint inhibitors; tertiary lymphoid structures
    DOI:  https://doi.org/10.3389/fimmu.2025.1554871
  3. Cell Oncol (Dordr). 2025 May 21.
    Embracing cancer immunotherapy with manganese particles.
    Ali Moosavi Zenooz, Majid Eterafi, Soheil Azarmi Giglou, Elham Safarzadeh.
      A substance integral to the sustenance and functionality of virtually all forms of life is manganese (Mn), classified as an essential trace metal. Its significance lies in its pivotal role in facilitating metabolic processes crucial for survival. Additionally, Mn exerts influence over various biological functions including bone formation and maintenance, as well as regulation within systems governing immunity, nervous signaling, and digestion. Manganese nanoparticles (Mn-NP) stand out as a beacon of promise within the realm of immunotherapy, their focus honed on intricate mechanisms such as triggering immune pathways, igniting inflammasomes, inducing immunogenic cell death (ICD), and sculpting the nuances of the tumor microenvironment. These minuscule marvels have dazzled researchers with their potential in reshaping the landscape of cancer immunotherapy - serving as potent vaccine enhancers, efficient drug couriers, and formidable allies when paired with immune checkpoint inhibitors (ICIs) or cutting-edge photodynamic/photothermal therapies. Herein, we aim to provide a comprehensive review of recent advances in the application of Mn and Mn-NP in the immunotherapy of cancer. We hope that this review will display an insightful view of Mn-NPs and provide guidance for design and application of them in immune-based cancer therapies.
    Keywords:  Cancer; Drug delivery; Immunotherapy; Manganese; Nanoparticle
    DOI:  https://doi.org/10.1007/s13402-025-01070-9
  4. Nat Commun. 2025 May 16. 16(1): 4579
    Inhibiting peptidylarginine deiminases (PAD1-4) by targeting a Ca2+ dependent allosteric binding site.
    Leslie A Dakin, Li Xing, Justin Hall, Weidong Ding, Felix F Vajdos, Jeffrey W Pelker, Simeon Ramsey, Paul Balbo, Parag V Sahasrabudhe, Mary Ellen Banker, Won Young Choi, Stephen W Wright, Jeanne S Chang, John M Curto, Jennifer E Davoren, Susan E Drozda, Kimberly F Fennell, Kentaro Futatsugi, Steve Kortum, Katherine L Lee, Shenping Liu, Frank Lovering, Jennifer A Nicki, John I Trujillo, Fabien Vincent, Mark E Schnute.
      Peptidylarginine deiminases (PAD1-4) are calcium dependent enzymes responsible for protein citrullination, a post-translational modification converting arginine residues to citrulline. Elevated levels of citrullinated proteins have been associated with rheumatoid arthritis, neurodegenerative diseases, and cancers. Though highly selective PAD4 inhibitors have been described, inhibitors to the broader family currently are limited to covalent substrate analogs. Herein, we describe an allosteric binding pocket common to PAD1-4 suitable for the identification of potent, non-covalent enzyme inhibitors. A ligand-based virtual screen is utilized to identify a PAD4 inhibitor for which surface plasmon resonance confirms target binding but non-competitively with a known PAD4 ligand. We further show through co-crystal structure analysis that the ligand binds PAD4 at an allosteric pocket resulting in stabilization of a catalytically inactive, calcium-deficient enzyme conformation. A ligand designed based on this site potently inhibits all four PAD isozymes and prevents protein citrullination in neutrophils with a broader protein repertoire than observed with a PAD4-selective inhibitor.
    DOI:  https://doi.org/10.1038/s41467-025-59919-4
  5. Nat Protoc. 2025 May 23.
    Integrating optical neuroscience tools into touchscreen operant systems.
    Patrick T Piantadosi, Oren Princz-Lebel, Miguel Skirzewski, Julie R Dumont, Daniel Palmer, Sara Memar, Lisa M Saksida, Vania F Prado, Marco A M Prado, Tim J Bussey, Andrew Holmes.
      Unlocking the neural regulation of complex behavior is a foundational goal of brain science. Touchscreen-based assessments of behavior have been used extensively in the pursuit of this goal, with traditional pharmacological and neurochemical approaches being employed to provide key insights into underlying neural systems. So far, optically based approaches to measure and manipulate neural function, which have begun to revolutionize our understanding of relatively simple behaviors, have been less widely adopted for more complex cognitive functions of the type assessed with touchscreen-based behavioral tasks. Here we provide guidance and procedural descriptions to enable researchers to integrate optically based manipulation and measurement techniques into their touchscreen experimental systems. We focus primarily on three techniques, optogenetic manipulation, fiber photometry and microendoscopic imaging, describing experimental design adjustments that we have found to be critical to the successful integration of these approaches with extant touchscreen behavior pipelines. These include factors related to surgical procedures and timing, alterations to touchscreen operant environments and approaches to synchronizing light delivery and task design. A detailed protocol is included for each of the three techniques, covering their use from implementation through data analysis. The procedures in this protocol can be conducted in as short a time as a few days or over the course of weeks or months.
    DOI:  https://doi.org/10.1038/s41596-025-01143-x
  6. Curr Mol Med. 2025 May 19.
    SMAC/DIABLO: A Guardian Angel in Boosting Anticancer Drug-Induced Apoptosis.
    Anuja Mishra, Swaroop Kumar Pandey.
      Apoptosis is an established hallmark of cancer. In normal conditions, apoptosis is strictly controlled; however, when it is not properly managed, it causes several complications, including cancer progression and drug resistance. SMAC/ Diablo (SMAC) is a mitochondrial protein that is released into the cytosol upon activation of BAX/BAK channels with apoptotic signals. SMAC protein interacts and neutralizes inhibitors of apoptosis (IAP) proteins and initiates the caspase cascade, which leads to apoptosis. SMAC is downregulated in several types of cancer, which led to the design of small-molecule inhibitors known as SMAC mimetics as new cancer therapeutics, and some of these molecules are in the clinical phase. It has also been shown that a combination of SMAC with standard anti-cancer drugs could be beneficial to drug-resistant cancer. Despite being a pro-apoptotic protein, it has been found that SMAC/Diablo is overexpressed in several types of cancers like lung, breast, bladder, cervix, pancreas, prostate, and colon, as well as in melanoma and glioma, and in cancer cells. Recently, we have reported that the overexpression of SMAC in cancers is essential for cell and tumor growth due to non-apoptotic regulation of phospholipid synthesis. The current review is focused on apoptotic and non-apoptotic functions of SMAC and its role in drug resistance.
    Keywords:  Cancer; SMAC/diablo; apoptosis; drug resistance.; drug target
    DOI:  https://doi.org/10.2174/0115665240380871250518032318
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