bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–08–10
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
  2. Mechanism of PISD/SPG7-mediated mPTP opening in necroptosis of inflammatory HaCaT cells induced by nano-zinc oxide.
  3. Detection assays of mitochondrial permeability transition pore: Current status and future prospects.
  4. Extracellular vesicle-mediated delivery of mitochondrial circRNA MTCO2 protects against cerebral ischemia by modulating mPTP-dependent ferroptosis.
  5. Mitochondrial function in intestinal ischemia-reperfusion injury: mechanisms and therapeutic perspectives.
  6. Cryogenic electron tomography and elemental analysis of mitochondrial granules in human retinal ganglion cells.
  7. Water-Soluble Peptoids with Two Different Binding Sites for Strong ATP Chelation.
  1. Cell Calcium. 2025 Jul 19. pii: S0143-4160(25)00065-X. [Epub ahead of print]131 103056
    Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
    Sara A Garcia, Anne M Neumaier, Michael Kohlhaas, Anton Xu, Alexander Nickel, Katharina J Ermer, Luzia Enzner, Christoph Maack, Vasco Sequeira, Christopher N Johnson.
      Mitochondrial calcium (Ca2+) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca2+ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca2+ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca2+ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca2+ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca2+ buffering. Fitting the Ca2+fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca2+ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca2+ binding was required for enhancement of MCU function.
    Keywords:  Calcium; Calmodulin; Calmodulin dependent kinase II (CaMKII); Mitochondrial calcium uniporter (MCU); Permeability transition pore (PTP)
    DOI:  https://doi.org/10.1016/j.ceca.2025.103056
  2. Toxicology. 2025 Aug 06. pii: S0300-483X(25)00217-3. [Epub ahead of print] 154258
    Mechanism of PISD/SPG7-mediated mPTP opening in necroptosis of inflammatory HaCaT cells induced by nano-zinc oxide.
    Menglei Wang, Qianwen Yang, Wantong Xiao, Yawen Luo, Jiawen Chen, Ziyi Tang, Yu Wei, Haiqing Li, Wanchun You, Yue Zheng, Li Li.
      Zinc oxide nanoparticles (ZNPs) are extensively used in cosmetics and topical medications and are considered safe for normal skin. However, patients with inflammatory dermatoses, who have an impaired skin barrier, may be at increased risk of percutaneous exposure to ZNPs. Limited research currently exists on the percutaneous toxicity of ZNPs in such conditions. Therefore, this study aimed to evaluate the safety of ZNPs in inflammatory dermatoses. ZNP treatment increased inflammatory human immortalised keratinocyte (HaCaT) cell death and significantly elevated phosphorylated mixed lineage kinase domain-like protein (p-MLKL) protein expression in a concentration-dependent manner, showing that ZNPs trigger necroptosis in HaCaT cells. Further exploration revealed that ZNPs induced mitochondrial swelling and rupture and abnormal opening of the mitochondrial permeability transition pore (mPTP) in inflammatory HaCaT cells as well as decreased the expression of spastic paraplegia 7 (SPG7), a critical protein of the mPTP. Furthermore, phosphatidylserine decarboxylase (PISD) expression in the inner mitochondrial membrane (IMM) was significantly reduced. SPG7 overexpression reversed mPTP opening and necroptosis, whereas PISD overexpression directly upregulated SPG7 expression, inhibited mPTP opening, and reversed necroptosis. Our results indicate that ZNPs contribute to mPTP opening and mitochondrial swelling and rupture via the PISD/SPG7 pathway, an important mechanism leading to necroptosis in inflammatory HaCaT cells. Overall, this study highlights the potential hazards of ZNP exposure in patients with inflammatory dermatoses, reveals the mechanism of injury by which ZNPs induce skin toxicity, and provides data for future dermatotoxicological studies on ZNPs.
    Keywords:  Inflammatory dermatosis; Mitochondrial permeability transition pore; Necroptosis; Zinc oxide nanoparticles
    DOI:  https://doi.org/10.1016/j.tox.2025.154258
  3. Acta Histochem. 2025 Aug 04. pii: S0065-1281(25)00050-9. [Epub ahead of print]127(3): 152278
    Detection assays of mitochondrial permeability transition pore: Current status and future prospects.
    Dongyang Hong, Jiawei Huang, Sicheng Hu, Yawen Zheng, Yuhuan Wu, Ziyang Cao, Zijun Yan, Hongyang Zhang, Huanhuan Feng, Jinxia Wang, Lin Zou.
      The mitochondrial permeability transition pore (mPTP) is a supramolecular entity in the inner mitochondrial membrane composed of various protein complexes, which is a critical component in maintaining mitochondrial function and cellular homeostasis. In this review, we provide a comprehensive summary of the current detection techniques for mPTP, including spectrophotometry, patch clamping, fluorescent probes, and flow cytometry, which have the potential to reveal the status of mPTP and its roles in degenerative diseases, inflammation, tumors and other diseases. Additionally, we discuss promising new methods to detect mPTP including enhancement in precision, high sensitivity, multi-parameter analysis, and technological integration. These advances highlight new possibilities of clinical diagnosis and treatment for mitochondria-related diseases.
    Keywords:  Detection assays; Mitochondria; Mitochondrial permeability transition pore (mPTP)
    DOI:  https://doi.org/10.1016/j.acthis.2025.152278
  4. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00319-2. [Epub ahead of print]86 103806
    Extracellular vesicle-mediated delivery of mitochondrial circRNA MTCO2 protects against cerebral ischemia by modulating mPTP-dependent ferroptosis.
    Jialei Yang, Shipo Wu, Miao He.
      Ischemic stroke remains a major cause of mortality and long-term disability, with few effective neuroprotective treatments currently available. Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is increasingly recognized as a driver of neuronal damage. However, the mitochondrial mechanisms linking ischemia to ferroptosis remain poorly defined. Here, we identify circMTCO2, a mitochondria-encoded circular RNA, as a novel endogenous modulator of neuronal ferroptosis. CircMTCO2 expression is dynamically downregulated following cerebral ischemia/reperfusion both in vitro and in vivo. Mechanistically, circMTCO2 binds directly to adenine nucleotide translocase 1 (ANT1), a key component of the mitochondrial permeability transition pore (mPTP), thereby inhibiting mPTP opening and suppressing mitochondrial ROS (mtROS) release. Disruption of the binding site abolishes the circMTCO2-ANT1 interaction and eliminates the protective effects of circMTCO2. To restore and enhance this intrinsic defense mechanism, we developed a dual-targeting extracellular vesicle system (RVG-EVmt-RNA) capable of delivering circMTCO2 specifically to brain neuronal mitochondria. Systemic administration of RVG-EVmt-RNA attenuated mtROS production, reduced neuronal ferroptosis, decreased infarct volume, and improved neurological function in a mouse model of ischemic stroke, without inducing systemic toxicity. These findings establish circMTCO2 as a previously unrecognized mitochondrial circRNA that regulates ferroptosis by modulating mPTP activity, and provide proof of concept that organ-to-organelle circRNA delivery can be leveraged as a precision neuroprotective strategy for ischemic stroke.
    Keywords:  Extracellular vesicles; Ferroptosis; Ischemic stroke; Mitochondrial circRNA; Targeted delivery; circMTCO2
    DOI:  https://doi.org/10.1016/j.redox.2025.103806
  5. Mol Biol Rep. 2025 Aug 02. 52(1): 784
    Mitochondrial function in intestinal ischemia-reperfusion injury: mechanisms and therapeutic perspectives.
    Xuena Han, Zekun Lang, Xinghua Lv, Yang Xing, Min Hou, Zhiguo Tan, Yan Zhang, Yufang Leng.
      Intestinal ischemia-reperfusion injury is a common pathophysiological event in acute abdominal conditions, characterized by tissue damage, a systemic inflammatory response, and multiple organ dysfunction. Recent studies have highlighted the central role of mitochondrial dysfunction in the initiation and progression of intestinal ischemia-reperfusion injury. Mitochondria play a crucial role in energy metabolism, redox balance, and cell death signaling, making them significant targets for research and therapeutic interventions. Moreover, oxidative stress-induced mitochondrial dysfunction-manifested by excessive reactive oxygen species production, loss of membrane potential, and calcium imbalance-further exacerbates cellular damage and promotes inflammatory responses. This review systematically examines the pathological mechanisms through which mitochondria contribute to intestinal ischemia-reperfusion injury and explores potential therapeutic strategies targeting mitochondrial function. Future research should focus on integrating signaling pathway analysis with multi-level treatment strategies, fostering the translation of basic research into clinical practice, and ultimately providing both theoretical and practical frameworks for improving patient outcomes.
    Keywords:  Intestinal ischemia-reperfusion injury; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-025-10894-5
  6. Structure. 2025 Jul 25. pii: S0969-2126(25)00258-8. [Epub ahead of print]
    Cryogenic electron tomography and elemental analysis of mitochondrial granules in human retinal ganglion cells.
    Gong-Her Wu, Cathy Hou, Andrew Thron, Hirenkumar Rajendra Patel, Liam Spillane, Sanket Rajan Gupte, Serena Yeung-Levy, Sahil Gulati, Christopher Booth, Yaping Joyce Liao, Wah Chiu.
      Combining three-dimensional (3D) visualization with elemental analysis of vitrified cells can provide crucial insights into subcellular structures and elemental compositions in their native environments. We present a coordinated approach using cryogenic electron energy loss spectroscopy (cryoEELS) and cryogenic electron tomography (cryoET) to characterize the elemental distribution and ultrastructure of vitrified cells. We applied this method to examine calcium disposition in the mitochondria of cultured human retinal ganglion cells (RGCs) exposed to pro-calcifying conditions relevant to optic disc drusen pathology. Our cryoEELS analysis revealed mitochondrial granules with elevated calcium signals, offering direct evidence of mitochondrial calcification. Additionally, cryoET coupled with artificial intelligence-based analysis enabled quantification of the volume and spatial distribution of these calcium granules. This integrated workflow can be broadly applied to various cell types, facilitating the study of ultrastructure and elemental distribution in subcellular structures under diverse physiological and pathological conditions, as well as in response to therapeutic interventions.
    Keywords:  calcium; cryogenic electron energy loss spectroscopy; cryogenic electron tomography; elemental analysis; human retinal ganglion cell; mitochondrial granules
    DOI:  https://doi.org/10.1016/j.str.2025.07.010
  7. Chemistry. 2025 Aug 04. e202500693
    Water-Soluble Peptoids with Two Different Binding Sites for Strong ATP Chelation.
    Nicole Vorobyov, Galia Maayan.
      Adenosine Triphosphate (ATP) is the activator of many enzymes, including kinases, that play a significant role in various medical conditions such as cancer. Therefore, inhibiting ATP-dependent enzymes requires to disable its binding to enzymes, and this can be done by developing potent ATP chelators. Currently, there are two main types of chelators: one that binds ATP via zinc complexes of nitrogen-based ligands, such as 2,2';6',2″-terpyridine (Terpy), which target the phosphate ligands, and another one containing phenylboronic acid (PBA) to bind the diols within the ribose. Herein, we report on a unique chelation approach that combines these two binding strategies in one scaffold; we use peptidomimetic oligomers called peptoids that incorporate both Zn(Terpy) and PBA as strong, water-soluble ATP binding inhibitors. These peptoids demonstrated high affinity to ATP, where the highest is KD-ATP = 7.416 × 10-9 M, four times higher than the binding affinity of peptoids targeting only phosphates or only diols, and at least two orders of magnitude higher than known ATP chelators. Structural studies indicated that positioning both Terpy and PBA side chains close together on the scaffold increased ATP binding affinity, compared to spacing them apart.
    Keywords:  ATP binding; dual binding; kinases; peptoid; phenyl boronic acid; zinc terpyridine
    DOI:  https://doi.org/10.1002/chem.202500693
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