bims-miptne 2026-03-08 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–03–08
ten papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitochondrial Resilience: Unraveling the Triadic Interplay of Phosphocreatine, Cyclophilin D, and STAT3 in Heart Failure.
Mitochondrial permeability transition pore desensitization by a novel dispiranic derivative prevents cardiac reperfusion injury.
Computational identification of marine-derived inhibitors of Cyclophilin D and Protease-Activated Receptor-1 for the treatment of ischemic disease.
Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.
Advances in calcium signalling research for the diagnosis and treatment of depression.
Unconventional model organisms bend our view on mitochondrial cristae.
Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
O. fragrans flower ameliorates compound 48/80-induced pseudo-allergic reactions in vitro and in vivo.
Absolute dynamic and relative static: the relationship of glycolysis and OXPHOS in cancer development.
Aspartame exacerbates cerebral ischemia-reperfusion injury via mitochondrial dysfunction and ERK/CREB1 pathway suppression.

J Cardiovasc Transl Res. 2026 Mar 06. pii: 34. [Epub ahead of print]19(1):

Mitochondrial Resilience: Unraveling the Triadic Interplay of Phosphocreatine, Cyclophilin D, and STAT3 in Heart Failure.

Eskandar Qaed, Wu Liu, Waleed Aldahmash, Mueataz A Mahyoub, Haya A Elshafei, Zeyao Tang.

  Heart failure remains a major global health burden, with mitochondrial dysfunction recognized as a key contributor to its onset and progression. This review highlights three critical regulators of mitochondrial integrity phosphocreatine (PCr), cyclophilin D (CypD), and signal transducer and activator of transcription 3 (STAT3) and their coordinated roles in cardiac function. PCr is vital for sustaining myocardial energy balance, particularly under metabolic stress. CypD controls the mitochondrial permeability transition pore, regulating cell death pathways that contribute to cardiac injury. Beyond its classical nuclear actions, STAT3 supports mitochondrial respiration, biogenesis, and resistance to oxidative damage. Evidence reveals a functional interplay among these regulators, forming a protective network that preserves mitochondrial performance. Disruption of this network promotes energetic failure, mitochondrial injury, and heart failure progression. Targeting PCr metabolism, CypD activity, and STAT3 signaling may represent a promising therapeutic approach to enhance mitochondrial resilience and improve clinical outcomes in heart failure patients.

Keywords:  Cyclophilin D; Heart failure; Mitochondrial; Phosphocreatine; STAT3

DOI:  https://doi.org/10.1007/s12265-026-10756-w
Redox Biol. 2026 Feb 19. pii: S2213-2317(26)00095-9. [Epub ahead of print]92 104097

Mitochondrial permeability transition pore desensitization by a novel dispiranic derivative prevents cardiac reperfusion injury.

Giampaolo Morciano, Gaia Pedriali, Giulia Turrin, Cristina Algieri, Esther Densu Agyapong, Debora La Mantia, Chiara Bernardini, Giorgia Canini, Anna Fantinati, Elena Nicoletta Colarusso, Fabio Mollica, Daniela Ramaccini, Alessandra Pagliarani, Carlotta Giorgi, Elena Tremoli, Alessandro Arcovito, Salvatore Nesci, Claudio Trapella, Paolo Pinton.

Mitochondrial permeability transition pore (PTP) opening is a major determinant of cardiac ischemia/reperfusion (I/R) injury, contributing to cardiomyocyte death and impaired cardiac function following revascularization. Despite extensive research, effective pharmacological strategies targeting PTP remain limited. Here, we report the identification and characterization of a novel class of dispiranic small molecules designed to inhibit PTP opening by targeting the c subunit of FO-ATP synthase. Using a multidisciplinary approach combining chemical synthesis, cellular and mitochondrial assays, ex vivo cardiac models and in silico analyses, we identified compound 11d as a potent and selective PTP desensitizer. In living human cardiomyocytes, 11d inhibited PTP opening by approximately 70% at low micromolar concentrations without impairing mitochondrial bioenergetics under basal conditions. Mechanistically, 11d selectively inhibited Ca2+-activated F1FO-ATP synthase activity, consistent with PTP modulation, while sparing Mg2+-dependent ATP synthesis and succinate oxidase activity. Molecular docking and molecular dynamics simulations revealed stable binding of 11d within the canonical oligomycin-binding pocket of the ATP synthase c-ring, a finding corroborated by cellular thermal shift assays and subcellular fractionation showing preferential mitochondrial accumulation. Functionally, 11d significantly reduced cell death, mitochondrial reactive oxygen species (ROS) production and PTP opening in cardiomyocytes and endothelial cells subjected to hypoxia/reoxygenation (H/R). Importantly, in an ex vivo Langendorff rat heart model, 11d administration at reperfusion markedly improved cardiac functional recovery, reduced infarct-associated cell death and preserved myocardial architecture. Collectively, these results identify 11d as a promising lead compound for cardioprotection and support targeting the ATP synthase c subunit as a viable therapeutic strategy against reperfusion injury.

DOI: https://doi.org/10.1016/j.redox.2026.104097
J Mol Graph Model. 2026 Feb 20. pii: S1093-3263(26)00055-0. [Epub ahead of print]145 109329

Computational identification of marine-derived inhibitors of Cyclophilin D and Protease-Activated Receptor-1 for the treatment of ischemic disease.

Veeresh Sadashivanavar, Manjunath Madalageri, Raghavendra Kinnal, Krishnadas Nandakumar, Ruchi Verma, K Sreedhara Ranganath Pai.

  Myocardial infarction (MI) and stroke are examples of ischaemic diseases that continue to pose serious health risks since few specific treatments address the underlying molecular causes of these conditions, which include pathological thrombosis and mitochondrial dysfunction. In order to close this gap, we used an integrated in-silico method to find strong inhibitors for Protease-Activated Receptor-1 (PAR-1) and Cyclophilin D (CypD) from the structurally diverse CMNPD marine natural product library. To account for protein flexibility, our method combines High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP) docking with meticulous Induced Fit Docking (IFD). After undergoing 500 ns Molecular Dynamics (MD) simulations, the best candidate compounds showed remarkable structural stability with RMSD values between 0.6 and 1.7 Å. Strong binding affinities were found by thermal MM-GBSA calculations, with CMNPD29955 showing a ΔG of -63.146 kcal/mol towards CypD and CMNPD3572 and CMNPD22037 showing ΔG values of -96.24 and -98.092 kcal/mol against PAR-1, respectively. Lead molecules of each target were found to have important hydrophobic and hydrogen bonding interactions with crucial active site residues in MD modelling. The dynamic stability and energetic favorability of these chemicals were further confirmed by complementary techniques, including WaterMap, Principal Component Analysis (PCA), and Free Energy Landscape (FEL). In addition to CMNPD3572 and CMNPD22037 as potential PAR-1 antagonists, this work emphasises CMNPD29955 as a new lead inhibitor that targets mitochondrial dysfunction via CypD. To transform computational insights into effective and complementary therapeutic alternatives, lead optimisation, experimental validation, and preclinical assessment of these special marine-derived molecules will be crucial in the future.

Keywords:  Cyclophilin D (CypD); Free Energy Landscape (FEL); Ischaemic diseases; Marine natural compounds; Molecular Dynamics (MD) simulation; Principal Component Analysis (PCA); Protease-activated Receptor-1 (PAR-1)

DOI:  https://doi.org/10.1016/j.jmgm.2026.109329
Nat Commun. 2026 Mar 06.

Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.

Winnie Fernando, Jarama Clucas, Alberto Rizzo, Ramsay Singer, Emily Goode, Crescens Tiu, Scott Layzell, Joshua Konecnik, Rebecca Wilson, Sidonie Wicky John, Samuel Jouny, Naomi Guppy, Victoire Boulat, Jonathan Mannion, Maria Goicoechea, Shaun Tan, Sam Lawson, Chris Starling, Gabrielle Elshtein, Nivedita Ravindran, Anna B Montgomery, Rosa Andres-Ejarque, Mark Allen, Steven Lumbard, Fredrik Wallberg, Kai Betteridge, Ross Scrimgeour, David Robertson, George Ward, Martin Sims, Tomoko Smyth, Andre L Samson, James M Murphy, Daniela Kolarevic Ivankovic, Esther N Arwert, Dinis P Calado, Anita Grigoriadis, Matthew J Smalley, Alan Melcher, Syed Haider, Toby Lawrence, Ioannis Roxanis, Andrew N J Tutt, Tencho Tenev, Pascal Meier.

Immunotherapy has transformed cancer treatment, including early triple-negative breast cancer (TNBC), yet most patients with advanced TNBC fail to respond to immune checkpoint blockade (ICB) plus chemotherapy. Durable control likely requires not only tumour cell killing but also immunogenic cell death (ICD) that activates antitumour immunity. Using a Brca1⁻/⁻p53⁻/⁻ organoid-derived TNBC model that recapitulates the immune landscapes of basal-like tumours, we show that RIPK1-driven ICD synergises with anti-PD-1 therapy to induce durable tumour control and immune memory in immune-infiltrated tumours. Mechanistically, both tumour-intrinsic and stromal necroptosis are required. Deletion of Ripk1 or Mlkl in tumour cells, or Mlkl in the stromal compartment, markedly impairs therapeutic efficacy. Moreover, immunologically "cold" tumours can be rendered responsive to ICD-based therapy by STING agonists. These findings demonstrate that the benefit of IAP antagonism with checkpoint blockade critically depends on coordinated necroptosis in both tumour and stromal cells, underscoring the need to integrate tumour microenvironmental context when designing ICD-targeted immunotherapies.

DOI: https://doi.org/10.1038/s41467-026-70133-8
Ann Med. 2026 Dec;58(1): 2620329

Advances in calcium signalling research for the diagnosis and treatment of depression.

Lin Li, Mingli Yao, Jing Meng, Zhen Zhong, Nan Nan, Amir Hooman Kazemi, Jiale Guo, Chenyue Liu, Youming Jiang.

   BACKGROUND: The increasing global burden of depression underscores the need for novel therapeutic strategies beyond conventional antidepressants such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Given the substantial role of calcium signaling in the pathogenesis of psychiatric disorders, this review examines its critical involvement in depression to guide future research and clinical advancements.
RESULTS: We describe the activation mechanisms of key calcium pathways, including voltage-gated channels, N-methyl-D-aspartate receptor-gated channels, endoplasmic reticulum-mediated release, and store-operated calcium entry, and summarize evidence of their dysregulation in clinical depression and animal models.Furthermore, we discuss the potential of calcium signaling as a diagnostic and prognostic biomarker, highlighting how emerging insights in this field may support the development of targeted antidepressant therapies.
CONCLUSIONS: This review indicates that calcium signaling demonstrates potential as a diagnostic biomarker and a basis for targeted antidepressant therapies.

Keywords:  Depression; calcium channels; diagnosis and treatment; pathophysiological mechanisms; therapeutic targets and strategies

DOI:  https://doi.org/10.1080/07853890.2026.2620329
J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):

Unconventional model organisms bend our view on mitochondrial cristae.

Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.

  Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.

Keywords:   Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae

DOI:  https://doi.org/10.1242/jcs.264310
Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Int Arch Allergy Immunol. 2026 Feb 28. 1-24

O. fragrans flower ameliorates compound 48/80-induced pseudo-allergic reactions in vitro and in vivo.

Qian Chen, Yuan Gao, Zhuangzhuang Liu, Yunfeng Huang, Min Cai, Congyu Wu, Muqing Wang, Yilin Guo, Yun Qi.

INTRODUCTION: O. fragrans flower is a highly popular edible flower due to its long-lasting aroma. Although it has been reported to possess multiple activities, no study focused on its effects on Mrgpr-mediated mast cell activation.
METHODS: The ethanol extract of O. fragrans flower (OFE) was prepared and the analyzed by the NaNO2-Al(NO3)3-NaOH colorimetric method and HPLC. Compound 48/80 (C48/80) was used for activating Mrgpr signaling. Supernatant β-hexosaminidase level was assayed by using the fluorescence probe 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide. The levels of cytoplasmic Ca2+ (Ca2+[c]) and intracellular mitochondrial Ca2+ (Ca2+[m]) were determined by fluorescence probes Fluo-3 AM and rhod-2/AM, respectively. The Ca2+ level outside the mitochondria was indicated by the fluorescence probe Calcium Green-5N. C48/80-induced vascular leakage, scratching behavior, and hypothermia models were used for evaluating the in vivo effects of OFE.
RESULTS: The highly water-soluble flavonoid-rich OFE significantly inhibited C48/80-induced degranulation in LAD2 cells and primary rat peritoneal mast cells (RPMCs). It could rapidly and reversibly decrease Ca2+[c] level independent of the activation of Mrgpr signaling. Among four classical pathways responsible for Ca2+[c] removal, OFE failed to affect PMCA, SERCA, and NCX, but promoted the uptake of mitochondrial Ca2+. In vivo, OFE alleviated C48/80-induced vascular leakage, scratching, as well as hypothermia.
CONCLUSION: This study indicates, for the first time, that OFE is a mast cell stabilizer. It decreases Ca2+[c] to suppress mast cell degranulation by directly enhancing mitochondrial Ca2+ uptake. These findings may unveil a potential medicinal value of O. fragrans flower as a promising candidate for relieving mast cell activation-related diseases.

DOI: https://doi.org/10.1159/000551184
Cell Death Discov. 2026 Mar 05.

Absolute dynamic and relative static: the relationship of glycolysis and OXPHOS in cancer development.

Xingting Bao, Boru Hou, Zhong Guo, Lei Song, Hailin Chen, Qian Zheng, Yongqing Zhao, Dandan Gao, Chenlong Fan, Xiaoyang Xiong, Chao Sun, Jin Zhao.

For a significant period following the postulation of the Warburg effect, mitochondrial dysfunction and aerobic glycolysis were commonly accepted as the defining features of cancer. Currently, a deeper understanding of tumor metabolism has demonstrated that the energy phenotype of tumor cells is not solely glycolytic. Most cancer cells possess active mitochondria and still maintain the ability to undergo oxidative phosphorylation (OXPHOS) and utilize the tricarboxylic acid (TCA) cycle to support tumor growth. In this review, we examine the choice of energy supply pathways in tumor cells in both static and dynamic contexts. From a static standpoint, tumors contain cells that rely on glycolysis or OXPHOS for energy supply and demonstrate metabolic heterogeneity. Additionally, the simultaneous operation of glycolysis and OXPHOS establishes metabolic symbiosis. In contrast, cancer cells can also exhibit metabolic plasticity by dynamically shifting between glycolysis and OXPHOS to support tumor growth. This process is influenced by a variety of factors, such as the ever-changing tumor microenvironment, specific biological activities of tumor cells, and the effects of drug therapies. The relationship between glycolysis and OXPHOS suggests that in the process of cancer development, the stable state of energy metabolism is temporary, while the dynamic changes in energy metabolism are eternal, which is in line with the category of dialectical materialism and provides us with a new perspective for treating cancer.

DOI: https://doi.org/10.1038/s41420-026-02992-5
Ecotoxicol Environ Saf. 2026 Feb 27. pii: S0147-6513(26)00267-8. [Epub ahead of print]312 119938

Aspartame exacerbates cerebral ischemia-reperfusion injury via mitochondrial dysfunction and ERK/CREB1 pathway suppression.

Yan Bai, Ji Feng, Xiao-Yu Wu, Zhi-Sheng Yao, Yue-Tong Liu, Yu-Hong Li, Guo-Dong Lu, Kun Xue.

   BACKGROUND: Aspartame, a widely used non-nutritive sweetener, has been associated with potential neurotoxicity. However, it remains unclear whether aspartame consumption can exacerbate cerebral ischemia-reperfusion injury (CIRI), a major contributor to stroke outcomes, and the underlying mechanisms are poorly understood.
METHODS: In vivo, male C57BL/6 J mice were given free access to 0.1% or 0.2% (w/v, equivalent to human acceptable daily intake level) aspartame, for 7 days, followed by bilateral common carotid artery occlusion (BCCAO) to induce CIRI. In vitro, hippocampal neural stem cells (NSCs) were subjected to oxygen-glucose deprivation (OGD) with aspartame. Cell injury, general and mitochondrial reactive oxygen species (ROS) burden, and mitochondrial function were assessed. Gene Ontology (GO), KEGG enrichment, and protein-protein interaction (PPI) network analyses were performed to identify potential targets. The ERK/CREB1 signaling pathway was evaluated by western blotting and pharmacological modulation.
RESULTS: Aspartame significantly increased the infarct volume and aggravated neuronal damage in BCCAO-treated mice. In NSCs, aspartame, but not acesulfame or sucralose, selectively enhanced OGD-induced apoptosis, accompanied by mitochondrial depolarization and excessive ROS accumulation, while showing minimal effects under normoxia conditions. GO/KEGG and PPI analyses highlighted ERK/CREB1 as an important node in aspartame-induced neurotoxicity. Consistently, aspartame suppressed the phosphorylation of ERK1/2 and CREB1. The ERK activator LM22B-10 and mitochondria-targeted antioxidant Mito-TEMPO partially reversed mitochondrial dysfunction, apoptosis and ERK/CREB1 suppression. Additionally, aspartame increased the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and increased NF-κB p65 phosphorylation and reduced the proportion of Tuj1-positive cells, which were mitigated by ERK activation.
CONCLUSION: Aspartame exacerbates CIRI-associated injury in a stress-dependent manner, involving mitochondrial dysfunction, ROS accumulation, and ERK/CREB1 suppression. Future studies are warranted to explore the long-term neurobehavioral outcomes and validate these mechanisms in clinical scenarios.

Keywords:  Aspartame; Cerebral ischemia–reperfusion injury; ERK/CREB1 pathway; Mitochondrial dysfunction; Mitochondrial reactive oxygen species

DOI:  https://doi.org/10.1016/j.ecoenv.2026.119938