bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–08–30
eleven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Cryo-EM insights into isoform-specific properties of the IP3R2 channel.
  2. Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
  3. The role of chloride ions in serotonin transport.
  4. Ninjurin-1 mediates hepatic ischemia-reperfusion injury.
  5. Structural basis of GSDME pore formation and its regulation by S-palmitoylation.
  6. Calcium dysregulation in breast cancer progression: mechanisms of calcicoptosis and therapeutic implications.
  7. Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
  8. Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy.
  9. A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
  10. A binding-to-release strategy for targeted anticancer drug delivery.
  11. Formate reduces cardiac ischemia-reperfusion injury in murine ex vivo and in vitro models.
  1. Nat Commun. 2026 Jul 22. pii: 8929. [Epub ahead of print]17(1):
    Cryo-EM insights into isoform-specific properties of the IP3R2 channel.
    Mariah R Baker, Xiaoxuan Lin, Guizhen Fan, Ariel Martinez-Chavez, Larry E Wagner, Sundeep Malik, Tyler Allison, Briar Bell, Alexander B Seryshev, Julio Cordero-Morales, Matthew L Baker, David I Yule, Irina I Serysheva.
      Calcium release through inositol 1,4,5-trisphosphate receptors (IP3Rs) is a fundamental signaling mechanism that regulates diverse cellular processes. Among the three mammalian IP3R isoforms, IP3R2 is widely expressed, yet its structural basis for activation and regulation remains unclear. Here, we report cryo-EM structures of mammalian IP3R2 in ligand-free (closed) and Ca2+/IP3/ATP-bound (activated) states at 3.3 Å and 3.6 Å resolution, respectively. These structures define the architecture of IP3R2 and reveal conformational transitions associated with channel activation. Although the IP3-binding pocket is conserved, subtype-specific differences in IP3 affinity likely arise from conformational dynamics of the regulatory ARM2 domain. Comparative analyses of IP3R isoforms identify subtype-specific allosteric networks and domain motions that underlie differential regulation. We further define the ATP-binding site and, through mutagenesis and electrophysiology, establish the structural basis for ATP modulation of channel activity. Together, these findings reveal mechanisms of IP3R2 activation and subtype-specific regulation, providing a framework for understanding isoform-dependent Ca2+ signaling.
    DOI:  https://doi.org/10.1038/s41467-026-75806-y
  2. Sci Adv. 2026 Aug 28. 12(35): eaeg8792
    Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
    Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.aeg8792
  3. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2605760123
    The role of chloride ions in serotonin transport.
    Jiahui Huang, Annika Backer, Stacy Uchendu, Bethlehem Bekele, Chan Li, Qingyang Chen, Esam A Orabi, Robyn Stix, Jasper D Shide, Yuan-Wei Zhang, Gary Rudnick, Eva Hellsberg, Lucy R Forrest.
      The human serotonin (5-HT+) transporter SERT facilitates 5-HT+ transport into cells by coupling it to Na+ symport and K+ antiport. Although extracellular Cl- is also essential for transport, Cl- cotransport has been disputed, raising questions about the role of Cl- ions and why they are required. We show that Cl- gradients do not impact 5-HT+ accumulation, indicating that Cl- does not provide a driving force for uptake and arguing against stoichiometric Cl- symport. The presence of Cl- had only a small effect on Na+-mediated cytoplasmic pathway closure but markedly reduced the accessibility of residues in the extracellular pathway, consistent with modulation of the outward-facing states. Simulations illustrate that Cl- interacts strongly with a bound Na+ ion and stabilizes helix packing on the extracellular side. We propose that Cl- acts as an essential architectural cofactor by enhancing Na+ affinity and interactions between helices, thereby facilitating transport-related conformational transitions.
    Keywords:  biochemistry; ion-coupled transporter; molecular dynamics simulations; neurotransmitters; secondary active transport
    DOI:  https://doi.org/10.1073/pnas.2605760123
  4. Sci Adv. 2026 Aug 28. 12(35): eaeg9496
    Ninjurin-1 mediates hepatic ischemia-reperfusion injury.
    Jan Mossemann, Brunna X Martins, Yixuan Zhao, Fiorelle Aguilar, Daria Taskina, Claire J Hur, Diana Nakib, Allen Volchuk, Gang Ye, Danish M Ali, Ali Mirzaesmaeili, Iram Siddiqui, Ghazal Goodarzi, Philip J Bilan, Irma B Stowe, Nobuhiko Kayagaki, Sonya MacParland, Spencer A Freeman, Neil M Goldenberg, Benjamin E Steinberg, Blayne A Sayed.
      Lytic cell death pathways drive hepatic ischemia-reperfusion injury (IRI). The transmembrane protein ninjurin-1 (NINJ1) aggregates in the plasma membrane to permeabilize the cell during multiple cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1 mediates liver IRI and that its inhibition would mitigate injury. We found that NINJ1 is highly expressed in human liver tissue and that its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients. Using a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. We therefore position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for liver transplantation.
    DOI:  https://doi.org/10.1126/sciadv.aeg9496
  5. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2614339123
    Structural basis of GSDME pore formation and its regulation by S-palmitoylation.
    Gang Du, Julian F Ehrmann, Judy Lieberman, Hao Wu.
      Pyroptosis is defined as gasdermin-mediated lytic programmed cell death. Gasdermin E (GSDME), a substrate of the apoptotic caspase-3, can convert apoptosis into pyroptosis, with critical roles in antitumor immunity and chemotherapy-induced tissue damage. Despite its importance, the structural mechanism of GSDME pore formation and its regulation by posttranslational modifications remain largely unknown. Here, we present the cryo-electron microscopy (cryo-EM) structure at 3.16 Å resolution of the human GSDME N-terminal (NT) pore using proteins expressed from mammalian cells. The structure reveals a GSDME-NT pore assembled mainly as a 28-subunit homo-oligomer, and a dramatic conformational rearrangement from the autoinhibited state, with refolding of the two β-hairpins in each monomer to form a membrane-spanning β-barrel with an acidic conduit. Unexpectedly, we identify endogenous S-palmitoylation of C45, C168, and C180, required for membrane binding and pore formation. In addition, extra cryo-EM densities are visible adjacent to the C45 side chain, potentially corresponding to the flexibly linked palmitate chain. Structure-guided mutagenesis demonstrates that these palmitoylation sites synergistically control pore formation. The structure served as a molecular blueprint for analyzing cancer-associated mutations, known to disrupt GSDME function. These mutations cluster at functional hotspots in the oligomerization interfaces, membrane-contact regions, and the β-barrel, where they disrupt pore integrity. Collectively, our findings establish palmitoylation as an obligatory licensing step for membrane binding and pore formation, provide structural visualization of a palmitoylated gasdermin, and reveal how cancer-associated mutations impair pyroptotic function. This structure and these insights will be useful for developing strategies that target GSDME to treat cancer and inflammatory disease.
    Keywords:  S-palmitoylation; cancer-associated mutations; cryo-EM structure; gasdermin E; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2614339123
  6. Cancer Gene Ther. 2026 Aug 25.
    Calcium dysregulation in breast cancer progression: mechanisms of calcicoptosis and therapeutic implications.
    Yu-Ting He, Jun-Hui Yin, Zhuo-Ling Li, Wen-Jing Zhang, Zi-Hao Gu, Na-Min Yang, Kang Li, Yi Zhou, Liang Ji.
      Disruption of calcium ion (Ca2+) homeostasis represents a critical mechanism in breast cancer (BC) progression, with aberrant Ca2+ transport through store-operated Ca2+ entry pathways, plasma membrane channels, and membrane contact sites (MCSs) playing a significant role in malignant transformation, metastasis, and therapeutic resistance. This dysregulation involves complex interactions among endoplasmic reticulum Ca2+ storage systems, Ca2+-dependent signaling cascades, and specialized MCSs that facilitate abnormal Ca2+ transfer between cellular organelles. Of particular therapeutic relevance, calcicoptosis-a novel form of Ca2+ overload-induced cell death-exhibits remarkable selectivity for BC cells over normal tissues, offering promising avenues for therapy, particularly in aggressive subtypes with limited treatment options. The distinct Ca2+ handling properties of BC cells present opportunities for targeted interventions that exploit these vulnerabilities through pharmacological modulation of Ca2+ transport mechanisms. This review synthesizes current understanding of Ca2+-mediated pathways in BC and outlines a framework for developing precision medicine approaches that leverage Ca2+ dysregulation as both a biomarker and a therapeutic target, with the potential to transform treatment strategies for patients with treatment-resistant disease.
    DOI:  https://doi.org/10.1038/s41417-026-01076-x
  7. Cell Rep. 2026 Aug 27. pii: S2211-1247(26)00951-4. [Epub ahead of print]45(9): 117873
    Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
    Soumya Maity, Manigandan Venkatesan, Adhishree Chidambaram, Sukanthathulse Uthayabalan, Louis Tung Faat Lai, Nicholas D Clark, Abhinaya Lakkureddi, Karthik Ramachandran, Kristen Bentz, Ravi Ramalingam, Sanjana Sen, Moeez Akram, Susan T Weintraub, Brij B Singh, David Gius, Joseph A Baur, Arianne L Theiss, Jeffrey Caplan, Doreen Matthies, Peter B Stathopulos, Muniswamy Madesh.
      Mitochondrial magnesium (mMg2+) is essential for cellular metabolism and bioenergetics, yet the mechanisms governing its transport remain poorly understood. Although MRS2 constitutes the pore of the mMg2+ channel, the molecular machinery regulating its function is unknown. Here, unbiased proteomics identified the prohibitin (PHB) complex as a prominent MRS2-interacting partner. Integrated biochemical and functional analyses demonstrate that the conserved coiled-coil domain mediates MRS2 homo-oligomerization, whereas the C-terminal region of MRS2 interacts with PHB1 to promote channel activity. Quantitative calibration of mitochondria-targeted MagFRET sensors revealed maximal mMg2+ uptake (∼15 mM), which was markedly reduced in Phb1-deficient hepatocytes. Complementary loss- and gain-of-function studies establish PHB1 as a positive regulator of MRS2-mediated mMg2+ uptake without affecting MCU-dependent Ca2+ transport. In vivo, hepatic Phb1 deletion attenuated mMg2+ uptake and enhanced cellular bioenergetics. These findings identify PHB1 as an activator of the MRS2, advancing our understanding of mMg2+ uptake machinery and its role in metabolic regulation.
    Keywords:  CP: molecular biology; MCU; MRS2; PHB; bioenergetics; calcium; channel; endoplasmic reticulum; magnesium; metabolism; mitochondria; prohibitin; structure
    DOI:  https://doi.org/10.1016/j.celrep.2026.117873
  8. Nat Commun. 2026 Jul 22. pii: 8940. [Epub ahead of print]17(1):
    Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy.
    Janne Van Hauwenhuyse, Felien Reniers, Leentje Persoons, Sam Noppen, Casey E Wing, Ashley B Niesman, Ho Yee Joyce Fung, Els Vanstreels, Maarten Jacquemyn, Eline Boel, Ann Vankerckhoven, Yani Berckmans, Bert Kwanten, An Coosemans, Guy Van den Mooter, Yuh Min Chook, Wim Dehaen, Dirk Daelemans.
      Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition to Cys528 in the nuclear export signal binding groove of XPO1. Here, we describe a novel XPO1 inhibitor, FR-027, that targets Cys528 through nucleophilic aromatic substitution. In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Structural analysis of the XPO1-FR-027 complex reveals covalent modification of Cys528 and a closed-groove conformation that prevents degradation. FR-027 demonstrates potent on-target activity across multiple cancer cell types and delays disease progression while extending overall survival in xenograft and syngeneic models, including intracranial tumors. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs.
    DOI:  https://doi.org/10.1038/s41467-026-75741-y
  9. Science. 2026 Aug 27. 393(6814): eaeh7112
    A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
    Jiyi Pang, Aysha H Al-Ani, Komal M Patel, Yunzhuo Zhou, Samuel N Young, Jinjin Chen, Isabella Kong, Marilou Barrios, James A Rickard, Siqi Chen, Xiuquan Ma, Farzaneh Shojaee, Seong-Beom Kim, Siavash Foroughi, Wayne Cawthorne, Annette V Jacobsen, Asha Jois, Ashley L Weir, Lachlan W Whitehead, Pradeep Rajasekhar, Christopher R Horne, Ruqian Lyu, Lucy J Mather, Raymond K H Yip, Ellen Tsui, Imadh Azeez, Tao Tan, Weiwei Liang, Suresh Sivanesan, Andrew Metz, Ash Patwardhan, Natalie Shea, Guru Iyngkaran, Daniel Schneider, Alexander T Elford, William Beattie, Finlay Macrae, Gianmaria Liccardi, Henning Walczak, Yuxia Zhang, Oliver M Sieber, Tim Spelman, Lisa Giulino-Roth, Michael Christie, Yunshun Chen, Kelly L Rogers, Rory Bowden, Sandra E Nicholson, Kate E Lawlor, Edwin D Hawkins, Britt Christensen, Andre L Samson, James E Vince, James M Murphy.
      Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identified aberrant epithelial cell death signaling as an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation skewed epithelial cells into an M1-macrophage-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. Thus, aberrant epithelial cell death signaling represents a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.
    DOI:  https://doi.org/10.1126/science.aeh7112
  10. Nature. 2026 Aug 26.
    A binding-to-release strategy for targeted anticancer drug delivery.
    Zihao Wen, Mengxin Xu, Zijun Yan, Ziren Kong, Yupeng Wang, Pei Liu, Junyi Chen, Yanzhao Liu, Xi-Yang Cui, Tianyi Cen, Xinwei Li, Yuedan Zheng, Zichen Gu, Da Xu, Qiang Xu, Yaping Luo, Changlun Wang, Zhibo Liu.
      Drug conjugates, such as antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs), are often dependent on efficient receptor-mediated endocytosis for payload release1-3-supported by about 10% of targets4-7. For poorly internalizing targets, drug conjugates dissociate and clear rapidly, limiting efficacy. To overcome the limitation in the internalization-to-release (ITR) pattern, we introduce a binding-to-release (BTR) strategy that decouples drug release from endocytosis by positioning an electrophile for direct cleavage by a proximal nucleophilic residue within the binding pocket. To realize this, we developed phosphorus(V)-phenol exchange (PhoPEx), a sulfur(VI) fluoride exchange-inspired chemistry enabling release of various payloads. This platform demonstrated high specificity from in vitro to clinical specimens, achieving precise detection of fibroblast activation protein (FAP) expression in patient-derived lymph nodes. In therapeutic settings, the FAP-BTR-SMDC achieved 5.9-fold higher monomethyl auristatin E exposure (AUC0-120 h) in tumours than internalization-dependent FAP-ITR-SMDC, matching FAP-ITR-ADC levels while minimizing off-target release. This led to improved ratios: the tumour-to-blood ratio was 14.7- and 3.6-fold higher than that of FAP-ITR-SMDC and FAP-ITR-ADC, respectively, and the tumour-to-liver ratio was 55.1- and 58.7-fold higher, respectively. This biodistribution increased the maximum tolerated dose and led to near-complete tumour regression in various tumour models. We further extended BTR to programmed cell death ligand 1 (PD-L1) and an mRNA-display-derived FAP peptide, suggesting potential broad applicability. This work establishes a framework that overcomes the internalization barrier, broadening the target scope for therapeutic and diagnostic conjugates.
    DOI:  https://doi.org/10.1038/s41586-026-10971-0
  11. Am J Physiol Heart Circ Physiol. 2026 Aug 25.
    Formate reduces cardiac ischemia-reperfusion injury in murine ex vivo and in vitro models.
    Haley Garbus, Raihan Kabir, Obialunanma V Ebenebe, Priyanka Patel, Deepthi Ashok, Diego Quiroga, Samarjit Das, Brian O'Rourke, Mark J Crabtree, Mark J Kohr.
      Ischemic heart disease is a leading cause of death in the United States. We and others have demonstrated that nitric oxide (NO) signaling and associated protein S-nitrosation (SNO) play a key role in reducing ischemic injury in the heart. We also find that while females typically exhibit endogenous protection from ischemic injury, this protection is abrogated with the loss of the formate-generating enzyme alcohol dehydrogenase 5 (ADH5), but formate supplementation provided a rescue. Here, we investigate the cardioprotective efficacy of formate in male hearts. Hearts were Langendorff-perfused and subjected to IR injury with and without formate. Formate-mediated protection was also examined using an in vitro model of coverslip-induced ischemic injury to identify cardiomyocyte-specific effects. We found that formate increases post-ischemic protein SNO levels and yields protection from IR injury in both ex vivo and in vitro models. However, NO synthase inhibition blocked the formate-mediated increase in protein SNO in vitro, and attenuated protection from IR injury ex vivo. Furthermore, post-ischemic levels of tetrahydrobiopterin (BH4), a cofactor necessary for NOS function, were preserved in formate-treated hearts. Collectively, our findings suggest that formate is a potent cardioprotective agent that preserves post-ischemic BH4 levels, and enhances protein SNO levels through a NOS-dependent mechanism. These findings have significant implications for the clinical prevention and treatment of ischemic heart disease in males.
    Keywords:  Formate; Ischemia-reperfusion injury; one-carbon metabolism
    DOI:  https://doi.org/10.1152/ajpheart.00348.2026
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