bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–03–22
five papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. A preclinical candidate of cyclophilin D inhibition improves alcohol-associated liver injury.
  2. pH-responsive CaCO3 nanoplatform amplifies SDT via calcium overload-ROS loop for deep tumor therapy.
  3. Subcellular calcium dynamics and organelle perturbations in resistosome-mediated cell death.
  4. Antitumor Cytisine-Platinum(IV) Prodrugs Potentiate Crosstalk between Endoplasmic Reticulum and Mitochondria through Calcium Overload Accompanied by Immunogenic Cell Death.
  5. Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.
  1. Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00071-6. [Epub ahead of print]7(3): 102654
    A preclinical candidate of cyclophilin D inhibition improves alcohol-associated liver injury.
    Zhaoyi Che, Zhihui Luo, Dong Xiao, Fashu Ma, Haoxiong Zhou, Yali Song, Shanshan Guo, Yuan Yuan, Hao Wang, Ching-Pong Mak, Kwok-Fai So, Jia Xiao.
      Currently, no therapies are approved for alcohol-associated liver disease (ALD). Here, we identify cyclophilin D (CypD) as a critical mediator in the progression of ALD. We observe elevated expression of CypD in ALD patients and a corresponding mouse model. Hepatocyte-specific knockout of CypD mitigates hepatic mitochondrial dysfunction, steatosis, inflammation, and oxidative stress. Conversely, overexpression of CypD exacerbates hepatic mitochondrial stress. In vivo and in vitro experiments demonstrate that a CypD inhibitor, RN-0001, effectively and safely alleviates hepatic damage induced by ethanol exposure; these protective effects are absent in CypD-deficient mice. Biophysical assays indicate that RN-0001 directly binds to CypD. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) tests and first-in-human phase I clinical trial identify RN-0001 as a promising translational candidate for ALD therapy. Collectively, our study highlights the pathological role of CypD in ALD and introduces a preclinical candidate for its management. This study was registered at chictr.org.cn (ChiCTR2500106709).
    Keywords:  alcohol-associated liver disease; cyclophilin D; mitochondrial dysfunction; preclinical candidate
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102654
  2. iScience. 2026 Mar 20. 29(3): 115082
    pH-responsive CaCO3 nanoplatform amplifies SDT via calcium overload-ROS loop for deep tumor therapy.
    Miao Chen, Yan Wang, Yiran Niu, Xiaomin Chen, Hang Su, Liang Xia, Chunbao Liu, Junfen Zhou, Zhen Wang, Bao Li, Diyu Lu.
      Sonodynamic therapy (SDT) for deep-seated tumors is limited by tumor microenvironment (TME) barriers. We developed a hyaluronic acid (HA)-modified mesoporous calcium carbonate nanoplatform (HA/CaCO3@Ce6) to synergistically enhance calcium overload and SDT. The CD44-targeted nanoplatform demonstrated pH-responsive degradation in acidic TME, resulting in the release of Ca2+ and chlorin e6 (Ce6). The released Ca2+ induced mitochondrial calcium overload, causing 71% collapse in membrane potential and 1.6-fold increase in reactive oxygen species (ROS) generation, establishing a "Ca2+-ROS positive feedback loop." This synergy triggered robust immunogenic cell death (ICD), enhancing CRT exposure by 94.2%, HMGB1 release by 46.2%, and ATP decrease by 74.5%. In vivo, it achieved 90.9% tumor inhibition and 80% 60-day survival rate, alleviated tumor hypoxia, and inhibited tumor proliferation and angiogenesis. This "ion-interference SDT" paradigm overcomes the limitations of SDT through self-amplified ROS cycle and provides an effective strategy for treating deep-seated solid tumor with significant clinical translation potential.
    Keywords:  Applied science; Drug delivery system; Nanoparticles
    DOI:  https://doi.org/10.1016/j.isci.2026.115082
  3. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2523470123
    Subcellular calcium dynamics and organelle perturbations in resistosome-mediated cell death.
    Yi-Feng Chen, Kuan-Yu Lin, Ching-Yi Huang, Liang-Yu Hou, Enoch Lok Him Yuen, Wei-Che Jimmy Sun, Bing-Jen Chiang, Chin-Wen Chang, Hung-Yu Wang, Tolga Osman Bozkurt, Chih-Hang Wu.
      Plant nucleotide-binding domain leucine-rich repeat-containing (NLR) proteins act as intracellular immune receptors that assemble into resistosomes to execute immune responses. However, the subcellular processes during cell death following resistosome activation remain unclear. Here, we visualized the changes in calcium signaling and organelle behavior after activation of the NRC4 (NLR required for cell death 4) resistosome. We found that NRC4 membrane enrichment coincided with calcium influx. This is followed by sequential mitochondria and plastid disruption, endoplasmic reticulum fragmentation, and cytoskeleton depolymerization. Subsequent loss of plasma membrane integrity, nuclear shrinkage, and vacuolar collapse mark the terminal stage of cell death. Our findings reveal a spatiotemporally resolved cascade of subcellular events downstream of resistosome activation, providing mechanistic insight into the execution phase of plant immune cell death.
    Keywords:  NLR-required for cell death; calcium; hypersensitive cell death; nucleotide-binding domain leucine-rich repeat-containing protein; organelles
    DOI:  https://doi.org/10.1073/pnas.2523470123
  4. J Med Chem. 2026 Mar 20.
    Antitumor Cytisine-Platinum(IV) Prodrugs Potentiate Crosstalk between Endoplasmic Reticulum and Mitochondria through Calcium Overload Accompanied by Immunogenic Cell Death.
    Ruo-Xi Sang, Yang-Qi Wang, Xiu-Yuan Wu, Zhe Li, Xiao-Meng Liu, Cheng-Zhi Xie, Xin Qiao, Yu-Kuan Feng, Jing-Yuan Xu.
      Given the critical role of interorganellar communication in cancer malignancy, this study focuses on the regulatory mechanism of calcium signaling mediated by endoplasmic reticulum (ER)-mitochondria contacts in tumor cell apoptosis. A series of Pt(IV) prodrugs derivatives incorporating the natural compound cytisine (CYT) were designed and synthesized, among them, compound CP12 demonstrated significant antitumor activity. CP12 induces ER stress and mediates mitochondrial calcium overload via the IP3R1-GRP75-VDAC1 axis, thereby triggering the collapse of mitochondrial membrane potential, a burst of reactive oxygen species, and ultimately initiating the apoptotic program. Concurrently, CP12 causes dual damage to nuclear and mitochondrial DNA, activates the cGAS-STING pathway, reverses the immunosuppressive tumor microenvironment, and enhances immunogenic cell death (ICD). In vivo, CP12 effectively inhibits lung cancer growth and significantly reduces the characteristic hepatorenal toxicity associated with cisplatin. Through the triple synergistic mechanism of chemical damage, organelle dysfunction, and immune activation, CP12 achieves highly efficient and low-toxicity therapy for lung cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03562
  5. Nat Commun. 2026 Mar 19.
    Parkinson's disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer.
    Zhi-Hao Lin, Nai-Jia Xue, Yi Liu, Feng Zhang, Xiao-Li Si, Ran Zheng, Lu-Yan Gu, Yao-Lin Li, Yi Fan, Jun Tian, Wolfgang H Oertel, Hyemyung Seo, Jia-Li Pu, Bao-Rong Zhang.
      Mutations in the phospholipase A2 group VI (PLA2G6) gene have been linked to autosomal recessive Parkinson's disease (PD), yet the molecular mechanisms remain poorly understood. This study provides the in vitro and in vivo evidence, specifically in dopaminergic neurons derived from patients with PD, that PLA2G6 loss-of-function disrupts the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), a critical regulator of Ca2+ transfer and energy homeostasis. This study demonstrates that the PLA2G6 protein localizes to the MAM and physically associates with the IP3R1-GRP75-VDAC1 complex. PLA2G6 deficiency destabilizes this complex, accelerating IP3R1 degradation, which in turn reduces ER-mitochondria contacts and impairs Ca2+ transfer. Notably, introducing a MAM linker restores the phenotypes caused by PLA2G6 loss. In iPSCs-derived dopaminergic neurons from patients with PD harboring PLA2G6 mutations, the structural and functional disruption of the MAM is further confirmed, underscoring its role in PD pathogenesis. These findings uncover the pivotal function of PLA2G6 within the MAM and suggest that modulating inter-organelle contacts could be a therapeutic strategy for correcting PD's ion channel dysfunction and energy imbalances.
    DOI:  https://doi.org/10.1038/s41467-026-70752-1
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