bims-miptne 2025-09-07 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–09–07
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Reperfusion injury in STEMI: a double-edged sword.
The role and behavior of voltage-gated calcium channels in ischemia/reperfusion.
Primary immunodeficiency diseases, inflammation and mitochondrial dysfunction.
MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury.
Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma.
Current advancements in the investigation of mitochondria-targeting organic sensitizers in cancer immunotherapy.
Targeting FCRLA to induce necrosis in lung adenocarcinoma: a novel strategy for prognosis and therapy via MPT-Driven pathways.
Highlighting the Transition of Mitochondrial Cytochrome C by Immuno-transmission Electron Microscopy.
Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.

Egypt Heart J. 2025 Sep 05. 77(1): 83

Reperfusion injury in STEMI: a double-edged sword.

Krupa Sara Thomas, Divina Mariya Puthooran, Sudeep Edpuganti, Adi Lakshmi Reddem, Angela Jose, Subramanya Sri Mahesh Akula.

   BACKGROUND: ST-elevation myocardial infarction (STEMI) is a major cardiac event that requires rapid reperfusion therapy. The same reperfusion mechanism that minimizes infarct size and mortality may paradoxically exacerbate further cardiac damage-a condition known as reperfusion injury. Oxidative stress, calcium excess, mitochondrial malfunction, and programmed cell death mechanisms make myocardial dysfunction worse. Even with the best revascularization techniques, reperfusion damage still jeopardizes the long-term prognosis and myocardial healing.
METHODS: A thorough narrative review was carried out using some of the most well-known scientific databases, including ScienceDirect, PubMed, and Google Scholar. With an emphasis on pathophysiological causes, clinical manifestations, innovative biomarkers, imaging modalities, artificial intelligence applications, and developing treatment methods related to reperfusion injury, peer-reviewed publications published between 2015 and 2025 were highlighted.
MAIN BODY: The review focuses on the molecular processes that underlie cardiac reperfusion injury, such as reactive oxygen species, calcium dysregulation, opening of the mitochondrial permeability transition pore, and several types of programmed cell death. Clinical syndromes such as myocardial stunning, coronary no-reflow, and intramyocardial hemorrhage are thoroughly studied-all of which lead to negative consequences like heart failure and left ventricular dysfunction. Cardiac magnetic resonance imaging along with coronary angiography and significant biomarkers like N-terminal proBNP and soluble ST2 aid in risk stratification and prognosis. In addition to mechanical techniques like ischemia postconditioning and remote ischemic conditioning, pharmacological treatments are also examined. Despite promising research findings, the majority of therapies have not yet proven consistently effective in extensive clinical studies. Consideration of sex-specific risk factors, medicines that target the mitochondria, tailored therapies, and the use of artificial intelligence for risk assessment and early diagnosis are some potential future avenues.
CONCLUSION: Reperfusion damage continues to be a significant obstacle to the best possible recovery after STEMI, even with improvements in revascularization. The management of STEMI still relies heavily on early reperfusion, although adjuvant medicines that target reperfusion injury specifically are desperately needed. Molecular-targeted approaches, AI-driven risk assessment, and precision medicine advancements have the potential to reduce cardiac damage and enhance long-term outcomes for patients with STEMI.

Keywords:  Artificial intelligence; Cardioprotection; Ischemia–reperfusion injury; Mitochondrial dysfunction; No-reflow phenomenon; Oxidative stress; Primary percutaneous coronary intervention (PPCI); Reperfusion injury; STEMI

DOI:  https://doi.org/10.1186/s43044-025-00683-7
Cell Signal. 2025 Sep 02. pii: S0898-6568(25)00522-4. [Epub ahead of print]136 112107

The role and behavior of voltage-gated calcium channels in ischemia/reperfusion.

Yusuf Anil Ay, Emir Enis Yurdgulu, Yasin Bayir, Zekai Halici.

  Ischemia/reperfusion (I/R) injury is a pathological condition that arises from the complex interplay of multifaceted mechanisms such as calcium imbalance, oxidative stress, mitochondrial dysfunction, and inflammatory processes. Voltage-gated calcium channels (VGCCs) play a critical role in this pathogenesis by regulating calcium influx into the cell, thereby initiating a cascade of detrimental intracellular events. During the ischemic phase, depletion of ATP reserves leads to the dysfunction of calcium transport systems; in the reperfusion phase, the stimulation of VGCCs by reactive oxygen species (ROS) intensifies intracellular calcium overload. This accumulation triggers the opening of mitochondrial permeability transition pores, amplifies ROS production, and activates cell death pathways such as apoptosis, necrosis, and ferroptosis. This comprehensive review explores the structural subtypes and physiological functions of VGCCs in detail while broadly investigating their behavior under I/R conditions across various organ systems, including the cardiovascular, neurological, renal, and reproductive systems. The review focuses on the distinct roles of L-, T-, N-, and R-type VGCCs and examines current findings on tissue- and isoform-specific pharmacological blockade strategies. Experimental studies demonstrating the protective effects of VGCC inhibitors-such as nimodipine, mibefradil, and SNX-111-are critically evaluated along with their translational limitations. By integrating up-to-date mechanistic insights with preclinical and early clinical data, this review highlights VGCCs as promising molecular targets for preventing I/R injury. Future therapeutic strategies should focus on isoform-specific targeting, time-dependent administration, and organ-directed formulations to enhance efficacy and safety.

Keywords:  Calcium; Calcium channel blockers; Ischemia; Reperfusion; Voltage-gated calcium channels

DOI:  https://doi.org/10.1016/j.cellsig.2025.112107
Clin Immunol. 2025 Sep 02. pii: S1521-6616(25)00170-6. [Epub ahead of print] 110595

Primary immunodeficiency diseases, inflammation and mitochondrial dysfunction.

Salvatore Nesci, Francesca Oppedisano, Giovanni Romeo, Silvia Granata.

  Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders characterized by impaired immune function, leading to increased susceptibility to infections, autoimmunity, and malignancies. While traditionally defined by immune cell defects, emerging evidence highlights the critical role of inflammation in PID pathogenesis. This review explores the intricate relationship between mitochondrial dysfunction and inflammation in PIDs. We examine how genetic defects in PIDs disrupt immune homeostasis, promoting pro-inflammatory states through cytokine dysregulation. Additionally, we discuss the vicious cycle involving oxidative stress, mitochondrial dysfunction, and inflammation, emphasizing the contribution of mitochondrial ROS production, mtDNA damage, and inflammasome activation in sustaining chronic inflammation. Furthermore, we propose that impaired mitochondrial function -potentially through mechanisms involving calcium signalling, ATP synthase regulation, and mitochondrial permeability transition pore formation - may serve as a central link between immune deficiency and hyperinflammation in PIDs. Understanding these complex interactions may provide new insights into the pathogenesis of PIDs and open avenues for targeted therapeutic strategies to improve patient outcomes.

Keywords:  Inflammation; Mitochondria; Mitochondrial permeability transition pore; Primary immunodeficiency diseases; mtDNA

DOI:  https://doi.org/10.1016/j.clim.2025.110595
Eur J Pharmacol. 2025 Sep 03. pii: S0014-2999(25)00872-6. [Epub ahead of print] 178118

MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury.

Haibo Xie, Jingyi Zhao, Jian Chen, Rui Li, Hui Li, Qifeng Wu, Chen You, Jiaxiang Zhang, Bo Liang, Qixing Zhu.

  Vascular endothelial cells (ECs) damage is closely related to kidney injury. Our previous research revealed the involvement of interferon regulatory factor 1 (IRF1)-mediated PANoptosis of renal ECs in trichloroethylene (TCE)-induced immune kidney injury. However, how IRF1 regulates ECs PANoptosis remains unclear. In this study, we explored the mechanism of PANoptosis in renal ECs by introducing TCE-sensitized mice model, in vitro experiments and population studies. We found that serum tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) were associated with kidney and ECs injury in patients with occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). The combination of TNF-α and IFN-γ influences the opening of the mitochondrial permeability transition pore (mPTP) in human umbilical vein endothelial cells (HUVECs), thereby promoting the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). The inhibition of mPTP opening through the application of cyclosporin A (CsA) led to a decrease in the cytoplasmic release of mtDNA and a subsequent reduction in cellular PANoptosis. CsA administration not only mitigated renal damage but also inhibited PANoptosis in renal ECs and suppressed the expression of IRF1 and Z-nucleic acid-binding protein 1 (ZBP1). IRF1 suppression alleviated cellular PANoptosis, whereas concurrent ZBP1 overexpression rescued it. In summary, TNF-α combined with IFN-γ induced mitochondrial mPTP opening and facilitated mtDNA release. The presence of mtDNA enhances the intranuclear transcription of IRF1, which in turn upregulates ZBP1 expression. ZBP1 recognizes mtDNA and contributes to cellular PANoptosis.

Keywords:  Endothelial cell; Mitochondrial DNA; Mitochondrial permeability transition pore; PANoptosis; Trichloroethylene

DOI:  https://doi.org/10.1016/j.ejphar.2025.178118
Cell Res. 2025 Sep 03.

Targeting necrotic lipid release in tumors enhances immunosurveillance and cancer immunotherapy of glioblastoma.

Yapeng Ji, Junyao Jiang, Lei Hu, Peng Lin, Mingshan Zhou, Song Hu, Minkai Wang, Yuchen Ji, Xianzhi Liu, Dongming Yan, Yang Guo, Adwait Amod Sathe, Bret M Evers, Chao Xing, Xuelian Luo, Qi Xie, Weike Pei, Zhenyu Zhang, Hongtao Yu.

Tumors evolve to avoid immune destruction and establish an immunosuppressive microenvironment. Syngeneic mouse tumor models are critical for understanding tumor immune evasion and testing cancer immunotherapy. Derived from established mouse tumor cell lines that can already evade the immune system, these models cannot simulate early phases of immunoediting during initial tumorigenesis. We developed a syngeneic mouse teratoma model derived from noncancerous mouse embryonic stem cells and conducted a genome-wide CRISPR screen to identify genes that impact early phases of cancer immunoediting. We found that loss of pro-apoptotic tumor suppressor genes, including Trp53, increased necrosis in teratomas, releasing APOE lipid particles into the extracellular milieu. Infiltrating T cells drawn to tumor necrotic regions accumulated lipids and became dysfunctional. Blocking lipid uptake in T cells or reducing necrosis in teratomas by inactivating the mitochondrial permeability transition pore (mPTP) restored immunosurveillance. Because mouse teratomas were highly enriched for brain tissues, we next examined the tumor-immune interaction in human glioblastoma (GBM). Indeed, infiltrating T cells in TP53-mutated human GBM accumulated APOE and were dysfunctional. Anti-APOE and anti-PDCD1 antibodies synergistically boosted anti-GBM immunity and prolonged survival in mice. Our results link mPTP-mediated tumor necrosis to immune evasion and suggest that targeting the uptake of lipids released by necrotic tumor cells by infiltrating immune cells can enhance cancer immunotherapy.

DOI: https://doi.org/10.1038/s41422-025-01155-y
Biomater Sci. 2025 Sep 05.

Current advancements in the investigation of mitochondria-targeting organic sensitizers in cancer immunotherapy.

Rui Jing, Shuai Si, Siyu Zhu, Xiaoying Tang, Zhenqi Jiang.

Cancer immunotherapy has transformed oncological treatment paradigms, yet tumor resistance and immune evasion continue to limit therapeutic efficacy. Mitochondria-targeting organic sensitizers (MTOSs) represent an emerging class of therapeutic agents that exploit mitochondrial dysfunction as a convergent node for tumor elimination and immune activation. As central regulators of cellular metabolism, apoptotic signaling, and immune cell function, mitochondria serve as critical determinants of tumor progression and the immunological landscape within the tumor microenvironment (TME). This comprehensive review synthesizes the latest advances (2023-2025) in MTOS-mediated cancer immunotherapy, systematically examining the capacity of MTOSs to induce diverse forms of regulated cell death and orchestrate antitumor immune responses. MTOSs demonstrate remarkable versatility in triggering mitochondria-dependent apoptosis, immunogenic cell death (ICD), necroptosis, pyroptosis, ferroptosis, and autophagic cell death through strategic disruption of mitochondrial homeostasis. These sensitizers modulate key mitochondrial functions including membrane potential dynamics, reactive oxygen species (ROS) generation, electron transport chain integrity, and calcium homeostasis, thereby releasing damage-associated molecular patterns (DAMPs) that potently activate both innate and adaptive immunity. Current MTOS platforms encompass small-molecule sensitizers, polymeric nanocarriers, metal-organic complexes, and biomimetic systems, each offering distinct advantages in mitochondrial targeting and therapeutic efficacy. Clinical translation faces significant challenges including variable mitochondrial targeting efficiency due to transmembrane transport limitations and TME pH fluctuations, systemic toxicity risks from nonspecific metal ion release in metal-organic complexes, insufficient long-term biocompatibility evaluation, and the predominant reliance on simplified tumor models that inadequately reflect clinical heterogeneity and complex spatiotemporal dynamics of mitochondrial damage-immune remodeling interactions. Future research directions emphasize the multidisciplinary integration of synthetic biology, nanotechnology, and computational approaches to engineer next-generation intelligent sensitizer platforms with enhanced TME-adaptive capabilities, enabling precise mitochondrial intervention and immune modulation for improved cancer immunotherapy outcomes.

DOI: https://doi.org/10.1039/d5bm01193k
Front Immunol. 2025 ;16 1596179

Targeting FCRLA to induce necrosis in lung adenocarcinoma: a novel strategy for prognosis and therapy via MPT-Driven pathways.

Xiaoli Sun, Bowen Cai, Shusen Zhang, Xiaowei Cao, Zhen Wang, Zhigang Cai.

   Introduction: The induction of mitochondrial permeability transition-driven necrosis (MPTDN) is therapeutically relevant in various cancers. However, few studies have explored the role of MPTDN-related genes (MPTDNRGs) in lung adenocarcinoma (LUAD). Therefore, this study investigated the regulatory mechanisms of MPTDNRGs in LUAD.
Methods: This study was based on The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD), GSE31210, and MPTDNRGs. First, the genes obtained from TCGA-LUAD were intersected through differential expression analysis and weighted gene co-expression network analysis (WGCNA) to obtain the candidate FCRLA gene. An FCRLA knockdown cell model was constructed in vitro using LUAD cells, and cell-related phenotypic experiments, including proliferation and apoptosis, were performed. The integrity of the mitochondrial structure was observed using electron microscopy, and the mitochondrial membrane potential was detected using a JC-1 probe.
Results: A total of 82 candidate genes were identified by intersecting 3,231 differentially expressed genes with 566 key module genes. Subsequently, three prognostic genes (RASGRP2, CD79A, and FCRLA) were further screened. CD79A and FCRLA were significantly expressed in the LUAD group, whereas the opposite was true for RASGRP2. In vitro studies indicated that FCRLA knockdown significantly inhibited the proliferation of LUAD cells and induced necrosis in these cells. Electron microscopy found that the mitochondrial structure was disrupted after FCRLA knockdown. The JC-1 probe indicated that the mitochondrial membrane potential in the FCRLA-knockdown group was significantly reduced, suggesting impaired mitochondrial function.
Discussion: RASGRP2, CD79A, and FCRLA have been identified as being associated with MPTDN in LUAD cells. FCRLA knockdown may suppress mitochondrial permeability transition through specific pathways, thereby driving LUAD cell necrosis and providing potential targets for subsequent LUAD treatment.

Keywords:  FCRLA; lung adenocarcinoma; mitochondrial permeability transition driven necrosis; new strategy; risk model

DOI:  https://doi.org/10.3389/fimmu.2025.1596179
J Vis Exp. 2025 Aug 15.

Highlighting the Transition of Mitochondrial Cytochrome C by Immuno-transmission Electron Microscopy.

Kaili Chen, Shoubo Jiang, Meng Zhou, Haijun Li, Xiuli Yang, Jun Chen.

Protein location changes in the microstructure often present a precise regulation mechanism at the level of pathological organelles. How to accurately capture the location of this organelle protein transfer has positive significance and value for the diagnosis and treatment of diseases. Mitochondria play a central role in necrosis and the intrinsic pathway of apoptosis. Under normal conditions, cytochrome c (Cyt c) only exists between the inner and outer membranes of mitochondria and in the nucleus. When cells undergo apoptosis, the mitochondrial inner membrane permeability is altered, and Cyt c is released from mitochondria into the cytoplasm. In this study, a rat model of cerebral ischemia-reperfusion injury was established, and the micromorphological changes of neurons undergoing apoptosis were shown by immuno-transmission electron microscopy. Additionally, it shows the vision of immunogold labeling Cyt c transfer from the mitochondrial matrix to the cytoplasm after cerebral ischemia-reperfusion injury more precisely. The immuno-transmission electron microscopy technique presented in this protocol is suitable for the demonstration of any protein position transitions at the microscopic level.

DOI: https://doi.org/10.3791/68633
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122

Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.

Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.

  Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler

DOI:  https://doi.org/10.1073/pnas.2502483122