bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–03–02
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Opening of the Mitochondrial Permeability Transition Pore Mediated Myocardial Damage After Perinatal Asphyxia in Neonatal Rats.
  2. How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.
  3. BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.
  4. Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.
  5. A Critical Role of Intracellular PD-L1 in Promoting Ovarian Cancer Progression.
  6. Predictive circulating biomarkers of the response to anti-PD-1 immunotherapy in advanced HER2 negative breast cancer.
  7. Development of Small Interfering RNA Loaded Cationic Lipid Nanoparticles for the Treatment of Liver Cancer with Elevated α-Fetoprotein Expression.
  8. MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
  1. Fetal Pediatr Pathol. 2025 Feb 24. 1-19
    Opening of the Mitochondrial Permeability Transition Pore Mediated Myocardial Damage After Perinatal Asphyxia in Neonatal Rats.
    Zhixin Chen, Jianqin Chen, Yongheng Chen, Xiaoyi Fang.
       OBJECTIVES: This study investigated the mechanisms underlying myocardial damage after perinatal hypoxia.
    METHODS: An intrauterine hypoxia-ischemia model (I/U HI) and a hypoxia/reoxygenation (H/R) model were established. Myocardial damage, mitochondrial function, and mitochondria permeability transition pore (MPTP) opening were determined. The results, presented as means ± SD, were analyzed using SPSS.
    RESULTS: Intrauterine hypoxia induced cardiac damage, mitochondrial dysfunction, and MPTP opening in neonatal rats. H/R led to apoptosis and MPTP opening. cTnI and apoptosis-inducing factor (AIF) levels were positively correlated with the degree of MPTP opening. The larger degree of MPTP opening combined with the significant increases in the Ca2+, ROS, and decreases in mitochondrial membrane potential and ATP levels. The larger degree of MPTP opening combined with the stronger release of cytochrome c and AIF.
    CONCLUSIONS: Increased MPTP opening may play a crucial role in perinatal asphyxia-induced myocardial damage in neonatal rats.
    Keywords:  MPTP; Perinatal asphyxia; mitochondrial, rats; myocardial
    DOI:  https://doi.org/10.1080/15513815.2025.2466804
  2. Cells. 2025 Feb 11. pii: 257. [Epub ahead of print]14(4):
    How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production.
    Raquel Adams, Nasrin Afzal, Mohsin Saleet Jafri, Carmen A Mannella.
      Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.
    Keywords:  ATP synthesis; cristae; electron tomography; membrane topology; metabolic modeling; metabolite diffusion; mitochondria
    DOI:  https://doi.org/10.3390/cells14040257
  3. Cells. 2025 Feb 09. pii: 246. [Epub ahead of print]14(4):
    BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.
    Palaniappan Ramesh, Amal R Al Kadi, Gaurav M Borse, Maximilian Webendörfer, Gregor Zaun, Martin Metzenmacher, Fabian Doerr, Servet Bölükbas, Balazs Hegedüs, Smiths S Lueong, Joelle Magne, Beiyun Liu, Greisly Nunez, Martin Schuler, Douglas R Green, Halime Kalkavan.
      Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP.
    Keywords:  BCL-2 family; BCL-B; BOK; DTP; EMT; cancer; drug-resistance; invasiveness; mitochondrial permeabilization; persister phenotype
    DOI:  https://doi.org/10.3390/cells14040246
  4. Biomolecules. 2025 Feb 03. pii: 223. [Epub ahead of print]15(2):
    Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.
    Henry Politte, Lingaiah Maram, Bahaa Elgendy.
      The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases.
    Keywords:  MPC (mitochondrial pyruvate carrier); MPC inhibitors; drug design; energy metabolism; medicinal chemistry; metabolic disorders (e.g., diabetes, obesity, and cancer); neurodegenerative disorders; pyruvate transport; therapeutic target; virtual screening
    DOI:  https://doi.org/10.3390/biom15020223
  5. Cells. 2025 Feb 19. pii: 314. [Epub ahead of print]14(4):
    A Critical Role of Intracellular PD-L1 in Promoting Ovarian Cancer Progression.
    Rui Huang, Brad Nakamura, Rosemary Senguttuvan, Yi-Jia Li, Antons Martincuks, Rania Bakkar, Mihae Song, David K Ann, Lorna Rodriguez-Rodriguez, Hua Yu.
      Disrupting the interaction between tumor-cell surface PD-L1 and T cell membrane PD-1 can elicit durable clinical responses. However, only about 10% of ovarian cancer patients respond to PD-1/PD-L1 blockade. Here, we show that PD-L1 expression in ovarian cancer-patient tumors is predominantly intracellular. Notably, PARP inhibitor treatment highly increased intracellular PD-L1 accumulation in both ovarian cancer-patient tumor samples and cell lines. We investigated whether intracellular PD-L1 might play a critical role in ovarian cancer progression. Mutating the PD-L1 acetylation site in PEO1 and ID8Brca1-/- ovarian cancer cells significantly decreased PD-L1 levels and impaired colony formation, which was accompanied by cell cycle G2/M arrest and apoptosis induction. PEO1 and ID8Brca1-/- tumors with PD-L1 acetylation site mutation also exhibited significantly reduced growth in mice. Furthermore, targeting intracellular PD-L1 with a cell-penetrating antibody effectively decreased ovarian tumor-cell intracellular PD-L1 level and induced tumor-cell growth arrest and apoptosis, as well as enhanced DNA damage and STING activation, both in vitro and in vivo. In conclusion, we have shown the critical role of intracellular PD-L1 in ovarian cancer progression.
    Keywords:  intracellular PD-L1; ovarian cancer; progression
    DOI:  https://doi.org/10.3390/cells14040314
  6. Clin Transl Med. 2025 Mar;15(3): e70255
    Predictive circulating biomarkers of the response to anti-PD-1 immunotherapy in advanced HER2 negative breast cancer.
    Yuhan Wei, Hewei Ge, Yalong Qi, Cheng Zeng, Xiaoying Sun, Hongnan Mo, Fei Ma.
       BACKGROUND: Immunotherapy shows promise for treating advanced breast cancer, but only a few patients could respond. Predictive biomarkers from peripheral blood are urgently needed.
    METHODS: We designed a comprehensive 42-marker mass cytometry panel to profile the peripheral blood samples from 57 patients diagnosed with advanced HER2-negative breast cancer receiving anti-PD-1 combination therapy. Patients were categorized as responders and non-responders according to 6-month progression-free survival (PFS), followed by phenotypic and functional comparations to identify candidate predictive biomarkers. Longitudinal analysis of paired samples further revealed dynamic changes in these specific subpopulations.
    RESULTS: Non-responders exhibited significantly higher frequencies of CD39+ Tregs (adjusted p = .031) in the T-cell milieu at baseline, which exhibited a positive correlation with PD-1+ T cells in the NR group. Longitudinal assessment indicated a significant decrease of PD-1+ T cells and an increase of CD39+ Tregs following anti-PD-1 treatment, suggesting their potential role in immunotherapy resistance. In the myeloid compartment, responders showed significantly higher CCR2+ monocyte-derived dendritic cell frequencies than non-responders (adjusted p = .037). These cells were positively correlated with other dendritic cells in responders but negatively with naïve T cells in non-responders. Based on these two efficacy-related biomarkers, we developed an immunotherapy prognostic prediction model and confirmed its superiority in distinguishing patient PFS (p < .001).
    CONCLUSION: Peripheral CD39+ Tregs and monocyte-derived dendritic cells are correlated with immunotherapy response, serving as potential biomarkers to guide therapeutic choices in immunotherapy.
    KEY POINTS: CD39+ Tregs in peripheral blood are associated with poor response to anti-PD-1 immunotherapy in advanced breast cancer. Higher frequencies of CCR2+ monocyte-derived dendritic cells correlate with better immunotherapy outcomes. A predictive model based on CD39+ Tregs and monocyte-derived dendritic cells effectively distinguishes patient progression-free survival. Peripheral blood biomarkers offer a non-invasive approach to guide immunotherapy choices.
    Keywords:  CyTOF; PD‐1; breast cancer; immunotherapy; peripheral blood mononuclear cell; predictive biomarkers; systemic immunity
    DOI:  https://doi.org/10.1002/ctm2.70255
  7. ACS Bio Med Chem Au. 2025 Feb 19. 5(1): 78-88
    Development of Small Interfering RNA Loaded Cationic Lipid Nanoparticles for the Treatment of Liver Cancer with Elevated α-Fetoprotein Expression.
    Kongpop Duangchan, Nathachit Limjunyawong, Kamonlatth Rodponthukwaji, Teeranai Ittiudomrak, Mattika Thaweesuvannasak, Natsuda Kunwong, Chanatip Metheetrairut, Vorapan Sirivatanauksorn, Yongyut Sirivatanauksorn, Prawat Kositamongkol, Prawej Mahawithitwong, Chutwichai Tovikkai, Kytai T Nguyen, Chatchawan Srisawat, Primana Punnakitikashem.
      α-Fetoprotein (AFP) is an oncogenic glycoprotein that is overexpressed in most patients with liver cancer. Moreover, it significantly affects tumorigenesis and progression, particularly by inhibiting programmed cell death or apoptosis. The treatment of liver cancer with chemotherapy is currently still in use, but its toxicity is a major concern. Alternatively, targeted therapy, especially small interfering RNA (siRNA)-based therapeutics that utilize siRNA to suppress target gene expression, is a promising cancer treatment approach that can help reduce such drawbacks. However, transporting siRNA into cells is a challenge due to its ease of degradation and limited cell membrane permeability. To overcome this limitation, we fabricated cationic lipid nanoparticles (cLNPs) to deliver AFP-targeted siRNA (siAFP) to AFP-producing liver cancer cells. Our results illustrated that these nanoparticles had a high capacity for siRNA encapsulation (>95%) and entered the cancer cells efficiently. Cell internalization of siAFP-loaded cLNPs resulted in the silencing of AFP mRNA expression and led to increased apoptotic cell death by inducing caspase-3/7 activity. This suggested that our cLNPs could be used as a powerful siRNA delivery carrier and siAFP-loaded cLNPs might be a useful strategy for treating liver cancer in the future.
    DOI:  https://doi.org/10.1021/acsbiomedchemau.4c00061
  8. Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]
    MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
    Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.
      Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.
    Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒02 at 6:18.