bims-miptne 2025-11-30 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–11–30
fifteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.
MICU2 controls mitochondrial calcium signaling and migration in neurons during development.
NMR assignments of the human homodimeric mitochondrial ATP synthase inhibitor IF1.
A mitochondrial permeability transition-associated lncRNA signature predicts prognosis and the immune response in gastric cancer.
Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.
Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.
Cardiac SR-Mitochondria Contacts-Impact on Cardiac Physiology and Mitochondrial Fitness.
MAM-Mediated Mitochondrial Ca2+ Overload and Endoplasmic Reticulum Stress Aggravates Synaptic Plasticity Impairment in Diabetic Mice.
The pH Perspective of Cancer: From Warburg's Misconception to Therapeutic Targeting of pH Regulating Proteins.
NNT deficiency alters cardiac structure and function without impairing mitochondrial bioenergetics in aged mice.
Mitochondrial involvement in PC: improving therapeutic strategies.
The novel sphingosine-1-phosphate receptor modulator KRP-203 prevents myocardial ischemia-reperfusion injury by preserving mitochondrial function through activation of the RISK and SAFE signaling pathways.
Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure.
Mathematical Modeling of Cell Death and Survival: Toward an Integrated Computational Framework for Multi-Decision Regulatory Dynamics.
Targeted protein degradation in the transmembrane and extracellular space.

Mol Neurobiol. 2025 Nov 29. 63(1): 214

Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.

Rasoul Ebrahimi, Sara Hatami, Anahita Hashempoor, Soroush Oraee, Shakiba Salarvandian, Ali Faramarzi, Khadijeh Esmaeilpour.

  Mitochondrial calcium has emerged as a critical player in Alzheimer's disease (AD), closely linked to neuronal dysfunction and cognitive decline seen in patients. Intracellular calcium signaling is essential for processes like synaptic plasticity, neuronal survival, and differentiation. When this balance is disturbed, it can trigger early pathological changes in AD, including the accumulation of amyloid-β (Aβ) peptides and the development of neurofibrillary tangles (NFTs), the hallmark features of the disease. Calcium imbalance in mitochondria disrupts their function, leading to reduced adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS), and ultimately neuronal death. Aβ and tau act synergistically to further disturb calcium regulation, intensifying neurodegeneration. Excess mitochondrial calcium is also linked to altered activity of key calcium transporters, such as the mitochondrial calcium uniporter (MCU) and sodium/calcium/lithium exchanger (NCLX). Moreover, several genetic risk factors for AD, including ApoE4, PS1, PS2, and CALHM1, are known to influence intracellular calcium homeostasis. Building on this, the present study investigates how calcium dysregulation impairs mitochondrial function in AD. Understanding the mechanisms of calcium-induced mitochondrial dysfunction and identifying potential targets to control mitochondrial calcium levels could provide valuable insights for developing therapies against AD and other neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Amyloid β; Calcium; Mitochondria; Tau

DOI:  https://doi.org/10.1007/s12035-025-05465-5
Cell Rep. 2025 Nov 20. pii: S2211-1247(25)01355-5. [Epub ahead of print]44(12): 116583

MICU2 controls mitochondrial calcium signaling and migration in neurons during development.

Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky.

  Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise in primary cortical neurons, leading to neuronal overmigration in the cortex and behavioral changes at 2 but not 12 months. Consistently, mitochondrial calcium uptake is not significantly affected in the adult animal cortex. MICU2-deficient patient fibroblasts copy the mitochondria-confined calcium alteration in developing neurons. Thus, MICU2 is important during neurodevelopment, likely by regulating the mtCU, and is eliminated by brain maturation.

Keywords:  CP: cell biology; CP: neuroscience; MCU; MICU2; MICU3; anxiety; brain development; calcium signaling; mitochondria; neurodevelopmental disorders; neurons; radial migration

DOI:  https://doi.org/10.1016/j.celrep.2025.116583
Biomol NMR Assign. 2025 Nov 27. 20(1): 6

NMR assignments of the human homodimeric mitochondrial ATP synthase inhibitor IF1.

Julia Jerolamon, Nathan N Alder, Andrei T Alexandrescu.

  ATPase inhibitory factor 1 (IF1) is the only known endogenous, proteinaceous inhibitor of mitochondrial ATP synthase in mammals. The inhibitor forms an antiparallel coiled-coil, which binds ATP synthase through an N-terminal α-helix extension that is disordered in the free protein. Because the IF1 dimer affects mitochondrial bioenergetics through its modulation of ATP synthase, it is a therapeutic target for cancer and cardiac disease. Here, we report 1H, 13C and 15N NMR assignments for the mature dimeric form of human IF1. Secondary structure analyses based on chemical shifts and short-range NOE patterns indicate the N-terminal half of the 81-residue IF1 is intrinsically disordered, while the C-terminal half adopts a continuous α-helix. The chemical shift assignments for human IF1 provide a foundation for future mechanistic structure-function studies and NMR-based drug screening.

Keywords:  ATP synthase; ATPase inhibitor; Coiled-coil dimer; Mitochondria; PH-dependent oligomer

DOI:  https://doi.org/10.1007/s12104-025-10257-y
Hereditas. 2025 Nov 26.

A mitochondrial permeability transition-associated lncRNA signature predicts prognosis and the immune response in gastric cancer.

Hao Hu, Ya Song, Sixia Jiang, Feng Xie.



Keywords:  Gastric cancer; Immune infiltration; Long non-coding RNAs; Mitochondrial permeability transition; Prognostic model

DOI:  https://doi.org/10.1186/s41065-025-00615-0
Biomolecules. 2025 Nov 09. pii: 1572. [Epub ahead of print]15(11):

Mitochondrial Dysfunction in Cardiomyopathy and Heart Failure: From Energetic Collapse to Therapeutic Opportunity.

Nikola Pavlović, Petar Todorović, Mirko Maglica, Marko Kumrić, Katarina Vukojević, Zenon Pogorelić, Joško Božić.

  The heart's relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD+ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients.

Keywords:  bioenergetics; cardiomyopathy; heart failure; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/biom15111572
Biochem Biophys Res Commun. 2025 Nov 24. pii: S0006-291X(25)01760-7. [Epub ahead of print]794 153044

Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis.

Cai Sun, Liang Pan, Chengsi Tang, Yiyuan Liu, Sha Ran, Ying Li, Yan Shen.

  Acute pancreatitis (AP) is a multifactorial disease in which mitochondrial dysfunction plays a key role by triggering inflammatory cascades and necrotic cell death. Mitochondrial transplantation has been reported to alleviate AP, however its underlying mechanisms remain unclear. To investigate the effect of mitochondrial transplantation on macrophage during AP, we stimulated macrophages with supernatant of damaged pancreatic acinar cells to mimic the inflammatory microenvironment. Upon stimulation, macrophages exhibited an enhanced capacity to internalize exogenous mitochondria. These exogenous mitochondria restored mitochondrial function in damaged macrophages by maintaining mitochondrial membrane potential, suppressing excessive reactive oxygen species production, and restoring ATP levels. Furthermore, mitochondria transplantation significantly inhibited macrophages necroptosis, as evidenced by the decreased protein expression and phosphorylation levels of the necroptosis markers RIPK1 and MLKL in macrophages and pancreatic tissue, and decreased cell necrosis. In terms of inflammation, exogenous mitochondria suppressed macrophage polarization toward the pro-inflammatory M1 phenotype and reduced the expression of pro-inflammatory cytokines. Collectively, these findings demonstrate that macrophage-centered inflammatory regulation constitutes a central mechanism underlying the therapeutic effects of mitochondrial transplantation in AP, providing a theoretical foundation for developing mitochondria-based therapeutic strategies.

Keywords:  Acute pancreatitis; Macrophage; Mitochondrial transplantation; Necroptosis

DOI:  https://doi.org/10.1016/j.bbrc.2025.153044
Cells. 2025 Nov 11. pii: 1762. [Epub ahead of print]14(22):

Cardiac SR-Mitochondria Contacts-Impact on Cardiac Physiology and Mitochondrial Fitness.

Celia Fernandez-Sanz, Shey-Shing Sheu, Sergio De la Fuente.

  In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca2+) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca2+ uniporter, while others perform non-canonical roles, such as DRP1 acting as a bioenergetics regulator. The purpose of this review is to provide a comprehensive compilation of the proteins that have been reported to be enriched in cardiac MAMs. We aim to show how their positioning is crucial for proper cardiac physiology and fitness, as well as how mispositioning may contribute to cardiac diseases. Additionally, we will discuss the gaps in our understanding and identify the necessary components to fully comprehend physiological communication between the sarcoplasmic SR and mitochondria in cardiac tissue.

Keywords:  MAMs; SR; bioenergetics; heart; microdomains; mitochondria

DOI:  https://doi.org/10.3390/cells14221762
Brain Sci. 2025 Oct 28. pii: 1157. [Epub ahead of print]15(11):

MAM-Mediated Mitochondrial Ca2+ Overload and Endoplasmic Reticulum Stress Aggravates Synaptic Plasticity Impairment in Diabetic Mice.

Jie Zhang, Jie Jiang, Haocong Li, Junliang Deng, Wei Dong, Huidan Deng.

  Background: As a chronic threat to human and animal health, diabetes impairs cognition and synaptic plasticity through mechanisms that remain unresolved. This study aims to explore whether mitochondria-associated endoplasmic reticulum membrane (MAM)-mediated mitochondrial Ca2+ overload and endoplasmic reticulum stress plays an important role in high-glucose-induced synaptic plasticity damage in hippocampal neurons. Methods and Results: In diabetic mice, cognitive dysfunction was tightly linked to the synaptic plasticity impairment, manifesting as significant reductions in both mRNA and protein levels of PSD-95, GAP-43, and SYP. Concomitantly, aberrant increases in MAM number and structural alterations, along with pronounced up-regulation of Mfn2, were observed in hippocampal tissue from diabetic mice and cultured hippocampal neurons exposed to high glucose. High glucose also elevated MAM-located Ca2+ transporters (IP3R, GRP75, MCU, and VDAC1), provoking mitochondrial Ca2+ overload and activating ERS, particularly via the IRE1α pathway. Knockdown of Mfn2 ameliorated these high-glucose-induced MAM abnormalities, suppressed mitochondrial Ca2+ overload and ERS, and exerted a protective effect against high-glucose-induced synaptic plasticity damage. Application of the inhibitor MCU-i4 to block Ca2+ transport within MAM reduced high-glucose-induced mitochondrial Ca2+ overload, relieved ERS, and improved high-glucose-induced synaptic plasticity impairment. Application of the inhibitor 4μ8C to suppress the IRE1α pathway of ERS alleviated mitochondrial Ca2+ overload and improved high-glucose-induced synaptic plasticity impairment. Conclusions: High glucose elicits MAM dysregulation, which precipitates reciprocal mitochondrial Ca2+ overload and ER stress, jointly driving hippocampal synaptic plasticity impairment.

Keywords:  diabetes-associated cognitive dysfunction; endoplasmic reticulum stress; mitochondria-associated endoplasmic reticulum membranes; mitochondrial Ca2+ overload

DOI:  https://doi.org/10.3390/brainsci15111157
Crit Rev Oncol Hematol. 2025 Nov 25. pii: S1040-8428(25)00439-1. [Epub ahead of print] 105051

The pH Perspective of Cancer: From Warburg's Misconception to Therapeutic Targeting of pH Regulating Proteins.

Changxian Chen, Xuanzhi Wang, Tingting Yang, Xi Yuan, Na Liang, Ying Yang, Xiaorong Yang, Yixuan Pang, Yi Zhao, Chunming Li.

  The acidification of the tumor microenvironment is a hallmark of malignant tumors, resulting from the coordinated action of multiple pH-regulating proteins.pH-regulating Key molecules, including the sodium-hydrogen exchanger (NHE), bicarbonate transporters, monocarboxylate transporters (MCTs), V-type ATPase (V-ATPase), and carbonic anhydrases (CAs) play central roles in tumor metabolic reprogramming and microenvironmental acidification. This review re-examines the Warburg effect and proposes that cytoplasmic alkalinization is the critical switch that initiates aerobic glycolysis and inhibits oxidative phosphorylation. The review further analyzes the roles of pH-regulating proteins in tumor migration, invasion, and therapeutic resistance, and summarizes therapeutic strategies targeting these proteins. Finally, the review outlines future directions for multi-target synergistic interventions and clinical translation, thereby providing a theoretical foundation for developing novel precision therapies that target tumor pH regulation.

Keywords:  V-type ATPase; bicarbonate transporter; carbonic anhydrases; monocarboxylate transporters; pH-regulating proteins; sodium–hydrogen exchanger

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105051
Redox Biol. 2025 Nov 17. pii: S2213-2317(25)00448-3. [Epub ahead of print]88 103935

NNT deficiency alters cardiac structure and function without impairing mitochondrial bioenergetics in aged mice.

Ana P Dalla Costa, Claudia D C Navarro, Edilene S Siqueira-Santos, Rafaela Q S Velasco, João V F Rosada, Andréia R Salgado, Daniele M R Demolin, Luiz A C Passos, Anibal E Vercesi, Annelise Francisco, Roger F Castilho.

  Proton-translocating NAD(P)+ transhydrogenase (NNT) is highly expressed in cardiac tissue, where it physiologically supports mitochondrial NADPH production. However, under certain pathological conditions, NNT may shift toward consuming the mitochondrial NADPH pool. Although NNT has been implicated in redox homeostasis, its contribution to cardiac function during aging remains uncertain. In this study, we assessed cardiac morphology and function, as well as mitochondrial bioenergetics and Ca2+ handling, in NNT-deficient (Nnt-/-) mice and congenic wild-type controls (Nnt+/+) at adult (5 months), middle (12 months), and older (23 months) ages. NNT-deficient mice developed age-related cardiac hypertrophy, along with a moderately reduced ejection fraction and fractional shortening at older ages, suggesting left ventricular dysfunction. These changes were associated with increased mitochondrial H2O2 release under specific conditions, whereas mitochondrial bioenergetic parameters and Ca2+ retention capacity remained largely unaffected by the Nnt genotype at all ages. Our findings indicate that NNT plays a protective role in the aging heart by maintaining redox balance and that NNT deficiency may contribute to late-onset cardiac dysfunction without causing overt mitochondrial bioenergetic failure. These results provide insight into the potential cardiac consequences of pathogenic NNT variants in humans.

Keywords:  Aging; C57BL/6J mouse; Cardiac function; Mitochondrial bioenergetics; Nicotinamide nucleotide transhydrogenase (NNT); Nnt mutation

DOI:  https://doi.org/10.1016/j.redox.2025.103935
Front Pharmacol. 2025 ;16 1710923

Mitochondrial involvement in PC: improving therapeutic strategies.

Jiaxin Zhang, Chang Lou.

  Prostate cancer (PC) is a complex disease propelled by various molecular mechanisms. The role of mitochondria in PC has recently emerged as a significant research focus. Mitochondria, often referred to as the cell's powerhouses, are not only essential for energy production but also crucial for key cellular processes like apoptosis, oxidative stress, and metabolic reprogramming. Changes in energy metabolism, marked by an increased dependency on oxidative phosphorylation (OXPHOS), have been noted in PC cells, offering a potential therapeutic target. Moreover, specific mitochondrial DNA (mtDNA) mutations have been linked with advanced tumors and adverse patient outcomes in PC. The mitochondrial reactive oxygen species (ROS), the disruption of mitochondrial dynamics and the fine balance between pro-apoptotic and anti-apoptotic signals mediated by Bcl-2 family proteins have also been implicated in PC. Comprehending the complex interaction between mitochondria and PC biology offers substantial potential for creating innovative targeted therapeutic strategies. This review emphasizes the role of mitochondria in the occurrence and malignant progression of PC, as well as the potential of targeted interventions on mitochondria in developing treatments, which may improve the prognosis of PC patients.

Keywords:  apoptosis; membrane permeabilization; mitochondria DNA; mitochondrial dynamics; oxidative phosphorylation; prostate cancer; reactiveoxygen species

DOI:  https://doi.org/10.3389/fphar.2025.1710923
Cell Biol Toxicol. 2025 Nov 27. 41(1): 159

The novel sphingosine-1-phosphate receptor modulator KRP-203 prevents myocardial ischemia-reperfusion injury by preserving mitochondrial function through activation of the RISK and SAFE signaling pathways.

Nan Wu, Linyuan Wang, Shuang Yu, Xiaoqi Wei, Haomeng Xu, Shuang Xu, Pengyu Jia, Xiaowen Zhang.

  KRP-203, a novel agonist of sphingosine-1-phosphate receptors (S1PRs), has shown promise in treating in immune-related diseases by blocking lymphocyte recruitment to inflamed tissues. Although S1PRs are abundantly expressed in cardiomyocytes, the specific effects of KRP-203 on these cells remain poorly understood. Here, we investigated the impact and mechanisms of KRP-203 pretreatment on myocardial ischemia-reperfusion injury (MIRI) via its interaction with cardiomyocyte S1PRs. To evaluate the efficacy of KRP-203 administered before ischemia, three MIRI models (in vivo, ex vivo, and in vitro) were employed. Overall, KRP-203 pretreatment significantly improved left ventricular systolic function, lowered serum levels of creatine kinase MB isoenzyme and lactate dehydrogenase, mitigated myocardial histopathological damage, and reduced both infarct size and cardiomyocyte apoptosis in vivo. Similar protective effects were observed in the in vitro and ex vivo models. Additionally, KRP-203 was found to preferentially bind to S1PR1 over S1PR2 and S1PR3 in cardiomyocytes. Further analysis revealed that pretreatment with KRP-203 significantly lowered the concentration of reactive oxygen species (ROS), prevented mitochondrial permeability transition pore opening, boosted mitochondrial membrane potential (MMP), and increased phosphorylation of AKT, EKR, GSK-3β, JAK2, and STAT3. These effects were reversed by S1PR1 knockdown in cardiomyocytes. Moreover, knocking down S1PR1 in the heart abrogated the cardioprotective effects of KRP-203. In summary, the findings indicate that KRP-203 pretreatment alleviates MIRI independently of lymphocyte involvement. Mechanistically, KRP-203 selectively activates S1PR1 on cardiomyocytes, triggering the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways to maintain mitochondrial integrity. These findings provide fresh perspectives on the pharmacological properties of KRP-203.

Keywords:  Mitochondrial function; Myocardial ischemia–reperfusion injury; Reperfusion injury salvage kinase signaling pathway; Sphingosine-1-phosphate receptor agonist; Survivor activating factor enhancement signaling pathway

DOI:  https://doi.org/10.1007/s10565-025-10114-7
Cardiovasc Res. 2025 Nov 26. pii: cvaf206. [Epub ahead of print]

Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure.

Mengying He, Woan Ting Tay, Ningjing Song, Tian Liu, Shuxun Vincent Ren, Cansheng Zhu, Nkechi Onubogu, Ozgu Biler, Jia En Tan, Caitlin Keezer, Xingyu He, Anthony Pham, Shuyuan Sheng, Hao Ding, Junxin Lin, Lingjun Wang, Yigang Wang, Xinyang Hu, Yibin Wang, Chen Gao.

   AIMS: Alternative mRNA splicing is a significant part of transcriptome reprogramming during the pathological manifestation of heart diseases. Earlier studies have identified a muscle-specific isoform of RBFox1 (RNA binding fox-1 homolog 1) to be a key RNA splicing regulator in pressure overload induced heart failure. However, the physiological impact of RBFox1 in myocardial infarction (MI), and the downstream mRNA alternative splicing events during MI induced cardiac remodelling remains unknown.
METHODS AND RESULTS: Here we found RBFox1 expression was significantly decreased in Sprague-Dawley rat hearts post MI. Restoring the expression of RBFox1 prevented cardiac remodelling and dysfunction post MI characterized by improved cardiac function, reduced hypertrophy and fibrosis, associated with attenuated induction of cardiac stress marker genes. In cultured cardiomyocytes, expression of RBFox1 was sufficient to prevent hypoxia induced cell death measured by TUNEL staining and cleaved caspase 3, while inactivation of RBFox1 aggravated cardiac cell death. Mechanistically, we identified RBFox1 expression affected a broad spectrum of gene expression in post-MI hearts. In addition, a hypoxia-sensitive alternative splicing variant of Mbnl1 (Muscleblind-like 1) mRNA was identified to be regulated by RBFox1, resulting in the expression of a cell death related Mbnl1 isoform with 12 amino-acid deletion at the C-terminus (Mbnl1-ΔExon7). Strikingly, the selective inhibition of Mbnl1 Exon7 inclusion using anti-sense oligo protected the heart from myocardial infarction induced injury in vivo.
CONCLUSION: In summary, we have established a cardio-protective role of RBFox1 in myocardial infarction induced cardiac remodelling and dysfunction. Restoration of RBFox1 expression, and targeted modulation of its downstream alternative splicing target Mbnl1, is a potential therapeutic approach for cardiac dysfunction and remodelling in MI injured heart.

Keywords:   Mbnl1 ; RBFox1 ; Heart Failure; Myocardial Infarction; mRNA splicing

DOI:  https://doi.org/10.1093/cvr/cvaf206
Cells. 2025 Nov 14. pii: 1792. [Epub ahead of print]14(22):

Mathematical Modeling of Cell Death and Survival: Toward an Integrated Computational Framework for Multi-Decision Regulatory Dynamics.

Elena Kutumova, Ilya Akberdin, Inna Lavrik, Fedor Kolpakov.

  Mathematical modeling is essential for understanding the complex regulatory pathways governing cell death and survival, including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy, and immunogenic cell death (ICD)-a functional category comprising diverse morphological types capable of activating immune responses. The growing number of models describing individual signaling pathways poses the challenge of integrating them into a cohesive framework. This review aims to identify common components across existing ordinary differential equation models that could serve as key nodes to merge distinct signaling modalities. Proposed models highlight Bcl-2, Bax, Ca2, and p53 as shared regulators linking autophagy and apoptosis. Necroptosis and apoptosis are interconnected via TNF signaling network and modulated by caspase-8, c-FLIP, and NFκB, with RIPK1 acting as a critical hub directing pathway choice. Pyroptosis and apoptosis are co-regulated by NFκB, tBid, and caspases, while ferroptosis is modeled exclusively as an independent process, separate from other forms of cell death. Furthermore, existing models indicate that ICD intersects with necroptosis during oncolytic virotherapy, with pyroptosis in SARS-CoV-2 infection, and with apoptosis in the context of chemotherapy. Although several models address crosstalk between pairs of cell fate decisions, creating comprehensive frameworks that encompass three or more death modes remains an open challenge.

Keywords:  ODE-based modeling; apoptosis; autophagy; ferroptosis; immunogenic cell death; necroptosis; pyroptosis

DOI:  https://doi.org/10.3390/cells14221792
Science. 2025 Nov 27. 390(6776): eadx5094

Targeted protein degradation in the transmembrane and extracellular space.

Rongfeng Zhu, Heng Zhang, Peng R Chen.

Transmembrane and extracellular proteins play crucial roles in diverse cellular functions and communication, affecting the progression and treatment of various diseases by mediating vital cellular processes. Whereas targeted protein degradation (TPD) represents an advancing therapeutic modality that leverages cellular degradation machinery to eliminate proteins of interest, present strategies have been largely confined to intracellular targets. Now, emerging strategies toward transmembrane and extracellular proteins are rapidly expanding the horizon of this powerful technology. Here, we review TPD in the transmembrane and extracellular space (meTPD) and discuss platform technologies, features, applications, and limitations. We focus on the conceptual innovations used in developing the present meTPD technology as well as its potential value for biological research and therapeutic interventions.

DOI: https://doi.org/10.1126/science.adx5094