bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–11–02
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. UNI-494 treatment improves measures of renal dysfunction and cardiac pathology in male rats receiving L-NAME and angiotensin II.
  2. Development of a mitochondrial permeability transition-driven necrosis-linked lncRNA signature for forecasting prognosis and treatment of lung adenocarcinoma.
  3. Loss of Ezrin triggers mitochondrial dysfunction and oxidative stress, associated with neuronal cell death.
  4. Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
  5. The senescent synapse: A look at autophagy, calcium handling, and mitochondrial bioenergetics at the synapse in ageing and Parkinson's disease.
  6. Cardioprotective Mechanisms of Beta-Blockers in Myocardial Ischemia and Reperfusion: From Molecular Targets to Clinical Implications.
  7. Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
  1. Physiol Rep. 2025 Nov;13(21): e70634
    UNI-494 treatment improves measures of renal dysfunction and cardiac pathology in male rats receiving L-NAME and angiotensin II.
    Fiona Jing Min Ho, Clarice Jing Rou Siow, Hayat Aljaibeji, Miao Ding, Richard N Mitchell, Satya Medicherla, Guru Reddy, Shalabh Gupta, Gordon H Williams, Jose R Romero.
      Mitochondrial dysfunction is essential in the pathophysiology of both cardiovascular disease (CVD) and chronic kidney disease (CKD). Nicorandil, a nicotinamide nitrate derivative, has been used for years as a cardioprotective agent. It binds to sulfonylurea receptors, activating mitochondrial ATP-sensitive potassium channels (MitoKATP) and functioning as a Nitric Oxide (NO) donor. However, its clinical use is limited by gastrointestinal complications. UNI-494 is a novel nicotinamide ester derivative and selective MitoKATP channel activator that reverses mitochondrial dysfunction by closing the mitochondrial permeability transition pore (mPTP) and has renoprotective effects. However, its impact on preclinical models of cardiac and renal disease is unknown. Rodents given Nω-nitro-L-arginine methyl ester (L-NAME) to suppress NO synthase and angiotensin II (AngII) show substantial cardiac and renal damage with significant increases in blood pressure. We hypothesize that mitochondrial dysfunction contributes to the pathophysiology of cardiorenal damage in the L-NAME/AngII rat model and that UNI-494 would improve cardiovascular and renal parameters. We studied the in vivo impact of UNI-494 on cardiorenal damage in the L-NAME/AngII rat model. Treatment with UNI-494 significantly reduced L-NAME/AngII-induced albuminuria, KIM-1 levels, and cardiac injury, with no significant effect on blood pressure. Our data suggest that cardiorenal damage can be prevented by treatment with UNI-494.
    Keywords:  CVD (cardiovascular disease); N‐omega‐nitro‐L‐arginine methyl ester (L‐NAME); albuminuria; angiotensin II (ANG II); cardiac damage; cardiorenal disease; kidney injury molecule (KIM‐1); nicorandil
    DOI:  https://doi.org/10.14814/phy2.70634
  2. Transl Cancer Res. 2025 Sep 30. 14(9): 5534-5549
    Development of a mitochondrial permeability transition-driven necrosis-linked lncRNA signature for forecasting prognosis and treatment of lung adenocarcinoma.
    Weibin Luo, Dongfang Li, Da Yao.
       Background: Lung adenocarcinoma (LUAD) is a common malignancy with a poor prognosis due to its aggressive nature and metastatic potential. Mitochondrial permeability transition (MPT)-driven necrosis and long non-coding RNAs (lncRNAs) play crucial roles in cancer progression. This study aimed to build a MPT-driven necrosis-linked lncRNA signature for forecasting prognosis and treatment of LUAD.
    Methods: The publicly available data of LUAD were downloaded from The Cancer Genome Atlas (TCGA) database for investigating the key MPT-driven necrosis-related lncRNAs in LUAD. Then, an MPT-driven necrosis-related lncRNA signature was constructed and its predictive performance for forecasting LUAD prognosis was examined. Moreover, nomogram construction, pathway, immune infiltration, immunotherapy response, and drug sensitivity analyses were performed to explore the clinical value and potential mechanisms of the signature in LUAD.
    Results: Six MPT-driven necrosis-related lncRNAs that were linked with LUAD prognosis were identified, including LINC01150, SIGLEC17P, SNHG3, DRAIC, AC099850.4, and AC245041.1. An MPT-driven necrosis-linked lncRNA signature was then constructed by these six lncRNAs, which showed high performance in forecasting prognosis. Moreover, the signature was linked with the infiltration of multiple immune cells like macrophages, activated CD4 T cells, and neutrophils. Furthermore, low-risk patients displayed greater sensitivity to immunotherapy.
    Conclusions: The six-MPT-driven necrosis-related lncRNA signature may be a powerful biomarker for forecasting prognosis and immunotherapy response of LUAD.
    Keywords:  Lung adenocarcinoma (LUAD); long non-coding RNAs (lncRNAs); mitochondrial permeability transition (MPT); necrosis; prognosis
    DOI:  https://doi.org/10.21037/tcr-24-2051
  3. Cell Death Discov. 2025 Oct 27. 11(1): 490
    Loss of Ezrin triggers mitochondrial dysfunction and oxidative stress, associated with neuronal cell death.
    Giuliana Giamundo, Iolanda Carratù, Chiara Barone, Rossella De Cegli, Giovanna Trinchese, Maria Pina Mollica, Dario Antonini, Ivan Conte.
      EZRIN is a key player in assembling and coordinating molecular signaling, acting as a linker between receptors in plasma membrane and the actin cytoskeleton. High EZRIN expression level has been extensively studied and often associated with metastasis and cancer progression. Recent reports independently suggested associations between Ezrin and mitochondrial alterations or apoptotic processes, the mechanism by which Ezrin modulates these events remain largely unclear. Here we report that the lack of EZRIN-mediated EGFR internalization and translocation on mitochondria is critical for mitochondrial metabolism. Ezrin-deficient (Ezrin-/-) cells exhibit marked impairments in mitochondrial respiratory chain (MRC) activity. These cells also show significantly reduced ATP production and elevated mitochondrial ROS levels, revealing cell metabolism deficit. Furthermore, Ezrin loss induces mitochondrial ROS-mediated apoptosis. In vivo, Medaka fish lacking Ezrin display neuronal cell death associated with inflammation, which appear linked to the compromised mitochondrial metabolism and oxidative stress. Our findings reveal a key mechanism within endo-lysosomal signaling that involves Ezrin and the EGFR/TSC complex. both of which are essential for neuronal homeostasis. In conclusion, our data identify a novel molecular pathway in which the Ezrin/EGFR axis regulates mitochondrial metabolism, thereby supporting cellular energy balance and promoting neuronal cell survival.
    DOI:  https://doi.org/10.1038/s41420-025-02790-5
  4. Nat Commun. 2025 Oct 27. 16(1): 9481
    Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
    Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis, Franz Hagn.
      The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.
    DOI:  https://doi.org/10.1038/s41467-025-65363-1
  5. Curr Res Physiol. 2025 ;8 100166
    The senescent synapse: A look at autophagy, calcium handling, and mitochondrial bioenergetics at the synapse in ageing and Parkinson's disease.
    Shahzabe Mukhtar, Shikha Kataria, Gloria Cimaglia, Dayne Beccano-Kelly.
      The synapse is a vitally important physiological structure fundamental to electrochemical communication between neurones, and is required for basic and important functions we perform daily. Underpinning the normal physiological function of the synapse are crucial processes such as autophagy, calcium homeostasis, and mitochondrial bioenergetics, all of which are modified during ageing. It is necessary to understand how ageing affects these processes at the synapse, from a fundamental need to understand natural ageing, and in order to identify how these processes may become aberrant and indeed, pathological, in the context of ageing-related disorders, such as Parkinson's. This review addresses the importance of the aforementioned processes, autophagy, calcium homeostasis, and mitochondrial bioenergetics at the synapse in normal physiology, and discusses how they are altered during ageing, and in Parkinson's, an example of accelerated ageing.
    DOI:  https://doi.org/10.1016/j.crphys.2025.100166
  6. Int J Mol Sci. 2025 Oct 10. pii: 9843. [Epub ahead of print]26(20):
    Cardioprotective Mechanisms of Beta-Blockers in Myocardial Ischemia and Reperfusion: From Molecular Targets to Clinical Implications.
    Athina Nasoufidou, Marios G Bantidos, Barbara Fyntanidou, Christos Kofos, Panagiotis Stachteas, Alexandra Arvanitaki, Paschalis Karakasis, Marios Sagris, George Kassimis, Nikolaos Fragakis, Efstratios Karagiannidis.
      Ischemic heart disease remains the leading cause of death despite substantial advances in diagnosis, revascularization therapies, and risk-factor control. Beta-adrenergic receptor blockers (Beta-Blockers, BBs), long used to control heart rate, blood pressure, and reduce arrhythmic risk, may also confer cardioprotection through mechanisms beyond hemodynamic unloading. This review integrates an extensive range of preclinical, translational, and clinical studies to present a comprehensive overview of the cardioprotective effects of BBs in the context of myocardial ischemia and reperfusion injury. Mechanistic domains include modulation of redox homeostasis, attenuation of inflammation and neutrophil activation, preservation of mitochondrial integrity and anti-apoptotic signaling, improvement of endothelial function, and stabilization of calcium handling. Third-generation compounds, carvedilol and nebivolol, demonstrate additional antioxidant and vasodilatory benefits compared with first- and second-generation agents; however, no consistent class-wide effect exists across most pathways. The evidence base remains fragmented, often derived from agent- or context-specific studies in heterogeneous populations, with uncertainty surrounding optimal timing of intervention. By bridging mechanistic understanding with clinical outcomes, this review highlights the importance of standardized assessment of BB effects, the development of personalized treatment approaches, and the pursuit of future research to address ongoing translational gaps.
    Keywords:  apoptosis; beta-blockers; cardioprotection; endothelial function; inflammation; ischemia; ischemic heart disease; oxidative stress; reperfusion; translational research
    DOI:  https://doi.org/10.3390/ijms26209843
  7. Nat Cell Biol. 2025 Oct 31.
    Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
    Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.
      The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01799-3
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒02 at 16:50.