bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–04–20
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Mechanism of MCUB-Dependent Inhibition of Mitochondrial Calcium Uptake.
  2. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
  3. A conserved fungal effector disturbs Ca2+ sensing and ROS homeostasis to induce plant cell death.
  4. Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.
  5. Utilizing multi-omics analysis, a new signature has been identified and validated for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma, which is based on tumor mutation burden.
  6. PD-L1-Targeting Nanoparticles for the Treatment of Triple-Negative Breast Cancer: A Preclinical Model.
  1. J Cell Physiol. 2025 Apr;240(4): e70033
    Mechanism of MCUB-Dependent Inhibition of Mitochondrial Calcium Uptake.
    Neeraj K Rai, David R Eberhardt, Anthony M Balynas, Melissa J S MacEwen, Ashley R Bratt, Yasemin Sancak, Dipayan Chaudhuri.
      Mitochondrial Ca2+ levels are regulated to balance stimulating respiration against the harm of Ca2+ overload. Contributing to this balance, the main channel transporting Ca2+ into the matrix, the mitochondrial Ca2+ uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca2+ uptake, suggesting the mechanism of inhibition may involve more global domain rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca2+ transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca2+ uptake.
    Keywords:  EMRE; Förster resonance energy transfer; MICU1; calcium channels; ischemia‐reperfusion injury; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.1002/jcp.70033
  2. Sci Adv. 2025 Apr 18. 11(16): eadw1489
    Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
    Maximilian Sichrovsky, Denis Lacabanne, Jonathan J Ruprecht, Jessica J Rana, Klaudia Stanik, Mariangela Dionysopoulou, Alice P Sowton, Martin S King, Scott A Jones, Lee Cooper, Steven W Hardwick, Giulia Paris, Dimitri Y Chirgadze, Shujing Ding, Ian M Fearnley, Shane M Palmer, Els Pardon, Jan Steyaert, Vanessa Leone, Lucy R Forrest, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
    DOI:  https://doi.org/10.1126/sciadv.adw1489
  3. Nat Commun. 2025 Apr 14. 16(1): 3523
    A conserved fungal effector disturbs Ca2+ sensing and ROS homeostasis to induce plant cell death.
    Yunlong Lin, Chan Xu, Lili Li, Liqin Fan, Rui Li, Jiaxin He, Hongli Li, Wei Deng, Zhensheng Kang, Zhengguo Li, Yulin Cheng.
      Acting as a major Ca2+ sensor, calmodulin (CaM) activates target proteins to regulate a variety of cellular processes. Here, we report that CaM-target binding is disturbed by a fungal virulence effector PdCDIE1 (Penicillium digitatum Cell Death-Inducing Effector 1), which results into reactive oxygen species (ROS)-dependent plant cell death. PdCDIE1 is an evolutionarily conserved fungal effector that exhibits plant cell death-inducing activity and contributes significantly to pathogen virulence. PdCDIE1 interacts with a plant heat shock protein Hsp70 that is antagonistic to ROS-dependent plant cell death. Hsp70 is a bona fide target of CaM and its CaM-binding domain also interacts with N-terminal PdCDIE1. The interaction between CaM and Hsp70 in citrus fruit is disturbed during pathogen infection but recovered during ΔPdCDIE1 mutant infection. Application of a CaM inhibitor and silencing of CaM genes induce plant cell death and high levels of ROS as PdCDIE1 does. These results reveal a molecular framework of effector-triggered susceptibility which integrates Ca2+ sensing and ROS homeostasis to induce plant cell death.
    DOI:  https://doi.org/10.1038/s41467-025-58833-z
  4. Mol Cell. 2025 Apr 17. pii: S1097-2765(25)00196-0. [Epub ahead of print]85(8): 1487-1508
    Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.
    Brandon Chen, Costas A Lyssiotis, Yatrik M Shah.
      Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes. Membrane contact sites (MCSs) are critical for facilitating mitochondria-organelle communication, creating specialized microdomains that enhance the efficiency of metabolite and lipid exchange. MCS dynamics, regulated by tethering proteins, adapt to changing cellular conditions. Dysregulation of mitochondrial-organelle interactions at MCSs is increasingly recognized as a contributing factor in the pathogenesis of multiple diseases. Emerging technologies, such as advanced microscopy, biosensors, chemical-biology tools, and functional genomics, are revolutionizing our understanding of inter-organellar communication. These approaches provide novel insights into the role of these interactions in both normal cellular physiology and disease states. This review will highlight the roles of metabolite transporters, lipid-transfer proteins, and mitochondria-organelle interfaces in the coordination of metabolism and transport.
    Keywords:  endoplasmic reticulum; inter-organellar communication; mitochondria; organellar metabolism; organelle membrane contact sites
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.003
  5. Discov Oncol. 2025 Apr 16. 16(1): 539
    Utilizing multi-omics analysis, a new signature has been identified and validated for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma, which is based on tumor mutation burden.
    Dongguang Wang, Yan Wang, Yiqun Peng, Liang Peng.
      Immunotherapy is used extensively in treating non-small cell lung cancer (NSCLC) patients. Nevertheless, in contrast to lung adenocarcinoma (LUAD), the endeavors to develop effective targeted treatments for lung squamous cell carcinoma (LUSC) have not yielded positive outcomes. Hence, it is crucial to discover biomarkers for immunotherapy and investigate more potent treatments, which is an immediate requirement for individuals with LUSC. The LUSC somatic mutation data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Multivariate analysis was performed to create a signature related to tumor mutation burden (TMB). Next, we utilized the CIBERSORT algorithm to assess the correlation between TMB and immune infiltrates. Additionally, we identified prognostic immune cells of LUSC through Kaplan-Meier analysis. The TCGA and ICGC cohorts covered a combined total of 11 genes that were frequently mutated. SYNE1 and TTN mutation correlated with an increased TMB and suggested a positive clinical outlook. A TMB-related signature (SYNE1 and TTN) was constructed based on this. The outlook for the high-risk group in LUSC was considerably poorer than the low-risk group (p = 0.004). In LUSC, there was a correlation between the TMB-related signature and immune infiltrates, and a positive response to anti-PD-L1 therapy was observed in individuals with low-risk scores. Furthermore, based on Kaplan-Meier analysis, plasma cells were identified as predictive immune cells in LUSC samples. In conclusion, the GSEA examination demonstrated that the TMB-associated signature stimulated immune system-related signaling pathways. To sum up, the TMB-associated signature could be marker to anticipate the immune reaction in individuals with LUSC.
    Keywords:  Immune infiltrates; Immunotherapy; LUSC; SYNE1; TMB; TTN
    DOI:  https://doi.org/10.1007/s12672-025-02166-2
  6. Int J Mol Sci. 2025 Apr 02. pii: 3295. [Epub ahead of print]26(7):
    PD-L1-Targeting Nanoparticles for the Treatment of Triple-Negative Breast Cancer: A Preclinical Model.
    Wendy K Nevala, Liyi Geng, Hui Xie, Noah A Stueven, Svetomir N Markovic.
      Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Common treatments following surgical resection include PD-1-targeting checkpoint inhibitors (pembrolizumab), as 20% of tumors are PD-L1 positive with or without systemic chemotherapy. Over the last several years, our laboratory has developed nano-immune conjugates (NIC) in which hydrophobic chemotherapy drugs like paclitaxel (PTX) and SN38, the active metabolite of irinotecan, are made water soluble by formulating them into albumin-based nanoparticles (nab) that are hydrophobically linked to various IgG1 monoclonal antibodies, creating an antigen-targetable nano-immune conjugate. To date, we have successfully tested PTX containing NICs linked to either VEGF- or CD20-targeted antibodies in two phase I clinical trials against multiple relapsed ovarian/uterine cancer or non-Hodgkin's lymphoma, respectively. Herein, we describe a novel NIC created with either PTX or SN38 that is coated with anti-PD-L1-targeting antibodies for the treatment of a preclinical model of TNBC. In vitro testing suggests that the chemotherapy drug and antibody retain their toxicity and ligand binding capability in the context of the NIC. Furthermore, both the PTX and SN-38 NIC demonstrate superior anti-tumor efficacy relative to antibody and chemotherapy drugs alone in a PD-L1 + MDA-MB-231 human TNBC xenograft model, which could translate clinically to patients with TNBC.
    Keywords:  mouse xenograft model; nano-immune conjugate (NIC); programmed death ligand 1 (PD-L1); triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3390/ijms26073295
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