bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–09–27
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
  2. Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
  3. Protein S-nitrosylation in the heart: Mechanisms, physiological roles, and pathological remodeling.
  4. Heart Failure in Focus: Acute Presentation, Risk Factors and Integration of Artificial Intelligence.
  5. Increased extracellular fluid viscosity drives M2-like macrophage polarization to promote breast cancer progression and immunotherapy resistance.
  6. Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca2+ activity.
  7. Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
  8. Ultra-slow release of hydrophilic drugs via multilamellar-multivesicular liposomes formed by unsaturated phospholipids.
  1. Front Cell Dev Biol. 2026 ;14 1963467
    Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development.
    Xiaoqian Fu, Qianyi Huang, Huimei Wu, Lidan Liu.
      Mitochondrial Ca2+ homeostasis is a critical interface connecting ovarian cell signaling, energy metabolism, redox balance, and reproductive competence. Transient Ca2+ uptake into the mitochondrial matrix activates Ca2+-sensitive dehydrogenases, enhances reducing-equivalent generation, and supports oxidative phosphorylation. By contrast, sustained Ca2+ accumulation promotes reactive oxygen species production, membrane-potential collapse, mitochondrial permeability transition, and cell death. The identification of the mitochondrial calcium uniporter together with its regulators MICU1, MICU2, and EMRE, has established a molecular framework for mitochondrial Ca2+ influx. NCLX and its interacting protein TMEM65 contribute to Ca2+ efflux and determine recovery after individual Ca2+ transients. In ovarian cells and oocytes, endoplasmic reticulum (endoplasmic reticulum)-mitochondria contact sites, including the IP3R1-GRP75-VDAC1 axis, couple cytosolic Ca2+ signals to mitochondrial metabolism. Evidence from mouse, porcine, avian, zebrafish, Xenopus, and sea-urchin models implicates mitochondrial Ca2+ in follicular-cell survival, oocyte meiotic maturation, fertilization-associated Ca2+ oscillations, the oocyte-to-embryo transition, and early embryonic development. Obesity, aging, cryopreservation, heavy metals, environmental chemicals, and oxidative stress can disturb this system. However, mitochondrial Ca2+ dysregulation is not always readily separable from broader mitochondrial or ER dysfunction. Major limitations of the current literature include reliance on non-selective pharmacological agents, incomplete calibration of organelle-targeted indicators, insufficient temporal resolution, interspecies differences, and limited direct evidence from human oocytes. Future studies should integrate cell-type-specific genetic perturbation, quantitative multi-organelle Ca2+ imaging, mitochondrial bioenergetics, and long-term developmental assessment. Mitochondrial Ca2+ is a promising mechanistic node and candidate biomarker, but it is not yet a validated clinical target in reproductive medicine.
    Keywords:  ER-mitochondria contact; MCU; MICU1; NCLX; embryo development; fertilization; mitochondrial Ca2+; oocyte competence
    DOI:  https://doi.org/10.3389/fcell.2026.1963467
  2. J Physiol. 2026 Sep 24.
    Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Sung Gi Noh, Martin Picard, Abbey-Gale Mannings, Michael S Cohen, Dennis W Wolan, Terence E Ryan, Russell T Hepple.
      Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.
    Keywords:  mitochondrial permeability transition; mitophagy; muscle atrophy; muscle wasting; neuromuscular junction
    DOI:  https://doi.org/10.1113/JP291213
  3. Redox Biol. 2026 Sep 23. pii: S2213-2317(26)00413-1. [Epub ahead of print]97 104414
    Protein S-nitrosylation in the heart: Mechanisms, physiological roles, and pathological remodeling.
    Maxime Gouin-Gravezat, Doria Boulghobra, Antoine Grandperrin, Beatrice Alpha-Bazin, Olivier Cazorla, Cyril Reboul.
      Protein S-nitrosylation (SNO), a reversible nitric oxide (NO)-dependent post-translational modification to reactive cysteine residues, finely tunes cardiac excitation-contraction coupling, mitochondrial function, and stress responses. In cardiomyocytes, compartmentalized NO signaling via neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) isoforms regulates SNO of key proteins (e.g., RyR2, LTCC, SERCA2a, mitochondrial Complex I). Under physiological conditions, SNO modulates Ca2+ handling, myofilament sensitivity, and bioenergetics, while pathological SNO dysregulation, hypo-nitrosylation in heart failure (HF) with reduced ejection fraction or hypernitrosylation in HF with preserved ejection fraction, contributes to contractile dysfunction, arrhythmias, and mitochondrial impairment. Cardioprotective SNO (e.g., during ischemia-reperfusion) acts as a "redox shield", preventing irreversible oxidation of critical cysteines, whereas excessive or mislocalized SNO can be detrimental, this dynamic modification plays an essential role in maintaining cardiac function. However, disruption of NO bioavailability and redox balance during cardiovascular disease alters the cardiac S-nitrosoproteome, contributing to maladaptive signaling, mitochondrial dysfunction, contractile impairment, and pathological remodeling. Increasing evidence also highlights the dual nature of SNO exerts either protective or detrimental effects depending on the molecular context, subcellular localization, and disease stage. This review summarizes current knowledge on SNO mechanisms in the heart and discusses its roles in physiological cardiac function and major cardiac pathologies.
    Keywords:  Excitation contraction coupling; Heart failure; Nitric oxide; S-nitrosylation
    DOI:  https://doi.org/10.1016/j.redox.2026.104414
  4. J Cardiovasc Dev Dis. 2026 Aug 26. pii: 415. [Epub ahead of print]13(9):
    Heart Failure in Focus: Acute Presentation, Risk Factors and Integration of Artificial Intelligence.
    Imo A Ebong, Edidiong I Akpabio.
      Heart failure (HF) is a complex syndrome that consists of cardinal clinical symptoms in the context of distinct physical signs, and it is frequently accompanied by a plethora of comorbidities [...].
    DOI:  https://doi.org/10.3390/jcdd13090415
  5. Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01123-X. [Epub ahead of print]45(10): 118045
    Increased extracellular fluid viscosity drives M2-like macrophage polarization to promote breast cancer progression and immunotherapy resistance.
    Juan Zhang, Yulong Han, Huan Gao, Mi Zhang, Xiaoqian Gao, Yan Zhou, Lin Wang, Lin Nan, Binghe Xu, Ting Wen, Jin Yang, Feng Xu.
      Breast cancer progression and therapy resistance remain major clinical obstacles. Although extensive research has focused on biochemical signals within the tumor microenvironment (TME), the contribution of physical cues, particularly the viscosity of interstitial extracellular fluid (ECF), has been largely overlooked. Here, we provide mechanobiological evidence that elevated ECF viscosity in the TME drives immunosuppressive M2-like macrophage polarization, which in turn promotes breast cancer growth and metastasis. Notably, increased ECF viscosity contributes to resistance to anti-PD-1 immunotherapy. We demonstrate that high ECF viscosity skews macrophages toward a pro-tumoral phenotype through integrin-mediated mechanotransduction, which activates focal adhesion kinase (FAK) and downstream signal transducer and activator of transcription 3 (STAT3), along with extensive cytoskeletal remodeling and nuclear deformation. Collectively, these findings establish ECF viscosity as a critical physical and immunological regulator and suggest it as a potential biophysical therapeutic target in breast cancer.
    Keywords:  CP: cancer; FAK-STAT3 signaling; breast cancer; cytoskeletal remodeling; extracellular fluid viscosity; immunotherapy; macrophage polarization
    DOI:  https://doi.org/10.1016/j.celrep.2026.118045
  6. Nat Cancer. 2026 Sep 25.
    Stroke drives glioma progression through the emergence of tumor-associated astrocytes with reduced Ca2+ activity.
    Qi Ye, Christine Madamba, Junsung Woo, Tiffany J Choy, Kate F Wheeler, Jiangshan Zhan, Carlo D Cristobal, Catalina Spjut, Donghui Shin, Juyeon Jo, Roshan R Ailani, Joshua Smith, Khatri Latha, Akdes Serin Harmanci, Hari Krishna Yalamanchili, Marco Gallo, Kyuson Yun, Yana K Reshetnyak, Eunhee Kim, Yongsoo Kim, Ganesh Rao, Benjamin Deneen, Hyun Kyoung Lee.
      Epidemiological studies suggest that persons with a history of stroke are at increased risk of developing brain tumors, yet the mechanisms linking brain injury to glioma progression remain unclear. Here we show that stroke promotes tumor infiltration into injured brain regions in human and mouse glioma models, accompanied by reduced overall survival. Stroke induces remodeling of the tumor microenvironment, including the emergence of a distinct population of tumor-associated astrocytes (TAAs) with diminished Ca2+ activity at the invasive front and enrichment of tumor-associated microglia and macrophages (TAMs). Restoring TAA Ca2+ signaling or TAM depletion suppresses stroke-induced glioma progression, identifying both populations as critical mediators of the injury response. Mechanistically, we identified SLC4A4 as a key regulator of Ca2+ activity in TAAs and CCL2-mediated TAM recruitment. Collectively, our findings establish stroke-induced remodeling of astrocytic Ca2+ signaling and TAMs as drivers of glioma progression and link brain injury to malignant disease.
    DOI:  https://doi.org/10.1038/s43018-026-01238-8
  7. Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):
    Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
    Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.
      Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77023-z
  8. Nat Biomed Eng. 2026 Sep 23.
    Ultra-slow release of hydrophilic drugs via multilamellar-multivesicular liposomes formed by unsaturated phospholipids.
    Yuan Wang, Tianrui Xue, Matthew Torre, Yiyuan Han, Rachelle Shao, Daniel S Kohane.
      Maintaining therapeutic drug concentrations at a target site while limiting systemic exposure is difficult for hydrophilic drugs, which rapidly diffuse from the injection site. Liposomes are widely used carriers, yet designs based on rigid, saturated phospholipids aim to reduce membrane permeability but often yield modest loading and substantial burst release. Here we compared liposomes composed of phospholipids of identical chain length but varying unsaturation, prepared under matched conditions. Contrary to the expectation that unsaturation accelerates release, liposomes based on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) showed approximately 3-fold higher loading, 11-fold lower initial release and 4-fold lower release at 7 days than saturated analogues. These effects correlated with the emergence of multilamellar and multivesicular structures and extended across diverse hydrophilic drugs. In a rat sciatic nerve block model, tetrodotoxin-loaded liposomes produced 2-3 weeks of blockade without systemic toxicity, establishing a simple platform for sustained local delivery.
    DOI:  https://doi.org/10.1038/s41551-026-01793-6
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