bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–10–05
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca2+ signals.
  2. Mitochondrial dynamics and pore formation in regulated cell death pathways.
  3. Zn2 + alleviates ischemia/reperfusion injury in H9c2 cells by modulating mitochondrial biogenesis and dynamics via MCU.
  4. Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.
  5. Mitochondria as a Therapeutic Target in Metabolic Disorders.
  6. MitoQ reduces senescence burden in Doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage.
  7. Targeting Calcium Regulation for Heart Failure and Arrhythmia Therapeutics: A Critical Review.
  1. Br J Pharmacol. 2025 Oct 03.
    A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca2+ signals.
    Anna Lischnig, Yusuf C Erdoğan, Benjamin Gottschalk, Michael Gruber, Andrea Groselj-Strele, Sandra Burgstaller, Wolfgang F Graier, Roland Malli.
       BACKGROUND AND PURPOSE: The calcium ion (Ca2+) is a versatile cellular messenger regulating a variety of biological processes. Compounds modulating subcellular Ca2+ signals hold substantial pharmacological potential. Advances in fluorescent biosensors have revolutionised Ca2+ imaging. However, co-expression of targeted biosensors for simultaneous measurement of Ca2+ signals in multiple cellular compartments is still complicated by heterogeneous expression levels of the various sensors.
    EXPERIMENTAL APPROACH: We developed the ribosomal skipping-based quad-cistronic fluorescent biosensor system CARMEN, enabling high-content Ca2+ imaging across three compartments. CARMEN allows proportional co-expression of spectrally distinct Ca2+ biosensors: the near-infrared Ca2+ biosensor for the cytosol (NIR-GECO2G-NES), the green Ca2+ biosensor for mitochondria (CEPIA3mt) and the red Ca2+ biosensor for the endoplasmic reticulum (R-CEPIA1er), along with a Ca2+-insensitive blue fluorescent protein targeted to the nucleus (NLS-mTagBFP2), serving as a normalisation reference.
    KEY RESULTS: CARMEN allows spatiotemporal correlation of Ca2+ signals across the cytosol, endoplasmic reticulum and mitochondria, revealing distinct dynamics. We noted delayed mitochondrial Ca2+ uptake compared to the other compartments. We validated CARMEN across three cell types and tested two recently identified mitochondrial Ca2+ uniporter inhibitors (MCUis), MCUi4 and MCUi11, showcasing the potential of CARMEN for its application in pharmacological research. Our results show that while both MCUi4 and MCUi11 inhibited mitochondrial Ca2+ uptake in HeLa S3 cells, MCUi4 reduced cytosolic Ca2+ signals and oscillations, whereas MCUi11 had opposing effects.
    CONCLUSIONS AND IMPLICATIONS: CARMEN is a powerful tool for real-time, multiplexed analysis of compartment-specific Ca2+ signals, with the potential for automation in high-content drug screening.
    Keywords:  Ca2+ multiplexing; MCU inhibitors ; fluorescence microscopy; genetically encoded Ca2+ biosensors ; spatiotemporal Ca2+ imaging
    DOI:  https://doi.org/10.1111/bph.70211
  2. Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00219-1. [Epub ahead of print]
    Mitochondrial dynamics and pore formation in regulated cell death pathways.
    Lisa Hohorst, Uris Ros, Ana J Garcia-Saez.
      Mitochondria act as central hubs for cell death signaling. During apoptosis and regulated necrosis (pyroptosis, necroptosis, and ferroptosis), mitochondria undergo drastic changes including membrane permeabilization, fragmentation, and loss of membrane potential. However, dissection of the mechanisms underlying these processes is challenging because they involve remodeling of mitochondrial membranes coupled to the assembly of protein complexes whose dynamics are difficult to capture. We discuss progress in our understanding of mitochondrial alterations in cell death and highlight state-of-the-art experimental approaches to study them. We focus on advanced single-molecule and correlative microscopy methods which have recently provided unprecedented details about the dynamics and structure of protein complexes in mitochondria and their impact on membrane organization.
    Keywords:  apoptosis; correlative microscopy; mitochondria dynamics; mitochondrial outer membrane permeabilization (MOMP); pore formation; single-molecule microscopy
    DOI:  https://doi.org/10.1016/j.tibs.2025.09.001
  3. J Trace Elem Med Biol. 2025 Sep 26. pii: S0946-672X(25)00182-8. [Epub ahead of print]92 127769
    Zn2 + alleviates ischemia/reperfusion injury in H9c2 cells by modulating mitochondrial biogenesis and dynamics via MCU.
    Bingyu Wang, Bohan Xing, Luyao Huang, Xiaoyi Li, Xiyun Bian, Jinkun Xi.
       BACKGROUND: Zinc is an essential nutrient implicated in cardiovascular health. This study investigates whether Zn2+ protects H9c2 cells by regulating mitochondrial biogenesis, dynamics, and calcium homeostasis via the mitochondrial calcium uniporter (MCU).
    METHODS: The I/R model were established using simulated ischemia and reoxygenation as previous reported, and cells were then treated with MCU siRNA. Biochemical kits, inductively coupled plasma mass spectrometry (ICP-MS), RT-qPCR, and transmission electron microscopy were used to assess the effects of Zn2+ on cell viability, cytotoxicity, Zn2+ and ATP content, NAD⁺/NADH ratio, mtDNA copy number, and mitochondrial morphological changes following myocardial I/R. Confocal microscopy and fluorescence microscopy were used to observe the fluorescence changes of Zn2+, mitochondrial membrane potential, protein expression, and mitochondrial Ca2+. The effects of Zn2+ on protein expression levels were evaluated using molecular docking and Western blot analysis.
    RESULTS: Compared to the Control group, the I/R group exhibited decreased cell viability, and increased cytotoxicity. Intracellular and mitochondrial Zn2+ levels were reduced, accompanied by mitochondrial dysfunction and an increase in mitochondrial Ca2+ content. The expression levels of mitochondrial biosynthesis proteins SIRT1, PGC-1α, NRF1, and TFAM, mitochondrial fusion proteins OPA1, MFN1, and MFN2, as well as MCUb gene and protein expression were downregulated. Conversely, the expression of mitochondrial fission proteins DRP1 and FIS1, along with MCU, MICU1, and MICU2 proteins, was upregulated. Exogenous Zn2+ treatment reversed these alterations. MCU silencing by siRNA further enhanced the protection effects of Zn2+.
    CONCLUSIONS: I/R induced damage in H9c2 cells and mitochondrial dysfunction. Zn2+ protected H9c2 cells against I/R injury by regulating mitochondrial biogenesis, mitochondrial dynamics, and Ca2+ homeostasis via the MCU, with this protective effect potentially associated with the entire MCU complex.
    Keywords:  MCU; Mitochondrial biogenesis; Mitochondrial dynamics; Myocardial ischemia/reperfusion injury; Zinc ion
    DOI:  https://doi.org/10.1016/j.jtemb.2025.127769
  4. Exp Gerontol. 2025 Oct 01. pii: S0531-5565(25)00242-6. [Epub ahead of print] 112913
    Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.
    Ziyue Xie, Xinyu Zhang, Yu Li, Ruigong Zhu.
      Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.
    Keywords:  Cellular senescence; Mitochondrial dysfunction; Molecular mechanism; Organelle
    DOI:  https://doi.org/10.1016/j.exger.2025.112913
  5. Mini Rev Med Chem. 2025 Sep 29.
    Mitochondria as a Therapeutic Target in Metabolic Disorders.
    Youde Cai, Fang Gan, Yunzhi Chen, Qiansong He, Wei Chen, Zhongyong Peng, Ling Gong.
      Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.
    Keywords:  Mitochondria; bioenergetics; cellular signaling; metabolism; redox biology; therapeutic target.
    DOI:  https://doi.org/10.2174/0113895575403490250917111723
  6. Am J Physiol Heart Circ Physiol. 2025 Sep 30.
    MitoQ reduces senescence burden in Doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage.
    Hossein Abdeahad, Denisse G Moreno, Samuel Bloom, Lucas Norman, Lisa A Lesniewski, Anthony J Donato.
      Cardiovascular toxicity is one of the adverse consequences of chemotherapy, limiting its therapeutic application. Chemotherapeutics, such as doxorubicin (DOXO), induce endothelial dysfunction via genotoxic effects, and reactive oxygen species (ROS) and mitochondrial ROS (mtROS) generation. These mechanisms increase DNA damage and cellular senescence, a persistent cell cycle arrest promoting inflammation, which elevates future cardiovascular disease risk. The adverse impact of DOXO on endothelial function can be mitigated by the mitochondria-targeted antioxidant, MitoQ; however, its precise protective mechanism in endothelial cells (ECs) remains unclear. The present study hypothesizes that co-treating ECs with MitoQ and DOXO attenuates DOXO-induced mtROS, thereby reducing DNA damage, senescence, and inflammation. Mitochondrial superoxide levels, mitochondrial mass, DNA damage, and cellular senescence were assessed in human umbilical vein ECs (HUVECs) 48 hours after DOXO and/or MitoQ treatment. DOXO treatment increased mtROS production and reduced mitochondrial mass compared to the vehicle group. Co-treatment with MitoQ decreased mtROS production and preserved mitochondrial mass compared to DOXO alone. MitoQ Co-treatment prevented senescence induction in DOXO-treated HUVECs, evidenced by preventing increased mRNA expression for senescence markers and senescence-associated beta-galactosidase (SA-ꞵgal) activity, alongside higher cell proliferation (BrdU incorporation). Additionally, MitoQ co-treatment reduced DNA damage and telomere dysfunction (DNA damage signaling at telomeres) compared to DOXO alone. Collectively, these data suggest mtROS drives cellular senescence in ECs through increased DNA damage and telomere dysfunction. These findings provide insight into mechanisms underlying DOXO-induced endothelial dysfunction and support mitochondrial-targeted antioxidant treatment as a potential therapeutic to mitigate chemotherapy-induced cardiovascular toxicity.
    Keywords:  Cardiovascular toxicity; Doxorubicin; Endothelial cell senescence; MitoQ; Mitochondrial ROS
    DOI:  https://doi.org/10.1152/ajpheart.00568.2025
  7. Circulation. 2025 Sep 30. 152(13): 957-970
    Targeting Calcium Regulation for Heart Failure and Arrhythmia Therapeutics: A Critical Review.
    Gabriel Redel-Traub, Steven O Marx, Andrew R Marks.
      Despite advances in pharmacologic and procedural therapies, heart failure (HF) and cardiac arrhythmias remain significant global health burdens, highlighting the urgent need for novel therapeutic strategies. Defective Ca2+ handling in cardiac myocytes is recognized as a central pathogenic mechanism underlying both heart failure and atrial and ventricular arrhythmias. In this review, we critically assess the current state of research on Ca2+-handling proteins and their role in causing heart failure and arrhythmias, highlighting therapeutic implications. Recent paradigm-shifting discoveries, clinical trial outcomes, and challenges of targeting Ca2+-handling proteins are examined. As outlined in this review, an improved understanding of the relevant proteins and their differential expression and function in human health and disease is crucial for developing Ca2+ handling-targeted therapeutics that can fundamentally alter the natural history of heart failure and arrhythmias.
    Keywords:  arrhythmias, cardiac; calcium signaling; drug therapy; heart failure; ryanodine receptor calcium release channel; sarcoplasmic reticulum calcium-transporting ATPases
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.075150
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