bims-miptne 2025-12-21 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–12–21
ten papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Cyclophilin D reduces Ca2+ sequestration by complement 1q binding protein.
Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.
Stochasticity contributes to explaining minority and majority MOMP during apoptosis.
Ferutinin can form transient pores in lipid membranes in the presence of magnesium or calcium ions.
Mitochondrial membrane chromatography: Discovery of mitochondrial targeting modulators.
Study on Smac promoting mitochondrial pathway apoptosis and muscle tenderization during postmortem aging of Tibetan sheep meat.
Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
Comprehensive analysis of genes associated with necroptosis and pyroptosis in intestinal ischemia-reperfusion injury.
MRPL37 promotes hepatocellular carcinoma progression through modulating mitochondrial energy metabolism.
The role and interplay among Autophagy, Apoptosis, and ferroptosis in acute pancreatitis: mechanisms and therapeutic approaches.

Biochem J. 2025 Dec 16. pii: BCJ20253361. [Epub ahead of print]482(24):

Cyclophilin D reduces Ca2+ sequestration by complement 1q binding protein.

Oluwatobi Adegbite, Yetunde Adegbite, Catrin Pickering, David N Criddle, Lu-Yun Lian.

  Complement 1q binding protein (C1qBP) and cyclophilin D (CypD) are mitochondrial matrix proteins; C1qBP has been implicated in many cellular processes, including the regulation of oxidative phosphorylation, and CypD is widely associated with the regulation of mitochondrial permeability transition pore (mPTP) opening. In this study, C1qBP and CypD were shown, in vitro, to form a stable protein-protein complex. CypD-C1qBP interaction was disrupted by cyclosporin A and compromised by mutations of the CypD active site residues R55 and R82. AlphaFold protein modelling revealed that the large negatively charged surface of C1qBP binds to the positive surface of CypD. This electrostatically driven interaction was confirmed by the pH dependence of the protein-protein interaction, with lower affinities observed at higher pH values. C1qBP was shown to undergo conformational changes when bound to Ca2+ in vitro, conferring multiple Ca2+ interaction sites in a multi-phase process, thereby indicating that C1qBP may act as a Ca2+ sequester. In contrast, CypD binding to C1qBP diminished the Ca2+-induced conformational changes in C1qBP, lowering its Ca2+-binding capacity. Our findings suggest that C1qBP functions as a mitochondrial Ca2+ chelator, with its efficiency reduced by CypD, this most likely due to CypD and Ca2+ both competing for the same negative surface of C1qBP. The parallels between the features of CypD-C1qBP interaction and the regulation of Ca2+-dependent mPTP opening by CypD highlight a possible functional role of CypD which has so far been elusive.

Keywords:  C1qBP; calcium; cyclophilin D; mitochondria; permeability transition pore

DOI:  https://doi.org/10.1042/BCJ20253361
Cold Spring Harb Perspect Biol. 2025 Dec 19. pii: a041773. [Epub ahead of print]

Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.

David R Eberhardt, Dipayan Chaudhuri.

Calcium (Ca2+) is vital in hepatocyte metabolism and plays a dual role in liver mitochondrial function: Physiological Ca2+ stimulates respiration and mitochondrial dynamics-processes crucial for proper metabolic functioning. However, Ca2+ overload can be catastrophic, leading to mitochondrial dysfunction and the halt of metabolic processes. This dichotomy plays out in liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic liver disease (ALD), where excess lipid and alcohol, respectively, result in pathological changes in this precarious Ca2+ balance, impairing liver function and contributing to liver failure. In this review, we discuss the complex processes of Ca2+ signaling in hepatic mitochondria and how these processes are altered or fail in liver disease states.

DOI: https://doi.org/10.1101/cshperspect.a041773
Cell Death Dis. 2025 Dec 19. 16(1): 893

Stochasticity contributes to explaining minority and majority MOMP during apoptosis.

Jenny Geiger, Fabian Klötzer, Nadine Pollak, Gavin Fullstone, Markus Rehm.

Apoptosis dysfunction is linked to diseases like cancer and neurodegenerative disorders. A key event during apoptosis is mitochondrial outer membrane permeabilization (MOMP), which typically proceeds in a rapid all-or-none fashion. If MOMP occurs only in a subset of mitochondria (minority MOMP), it can be sublethal and contribute to tumorigenesis and cancer progression. Similarly, individual mitochondria escaping widespread MOMP (majority MOMP) can allow cancer cells to recover if apoptosis execution fails. How such heterogeneities in mitochondrial MOMP responsiveness arise within cells is incompletely understood. In particular, whether stochasticity in subcellular protein distributions and interactions across cytosol and mitochondria can realistically contribute to mitochondrial MOMP heterogeneity has not yet been studied. To assess this, we sequentially built and experimentally parameterized a particle-based, cell-sized model including cytosolic and mitochondrial compartments, and that featured a reduced interactome of MCL-1, BAK and tBID. High-performance computing enabled cell-scale simulations of protein distributions and interactions to understand how and under which conditions stochasticity could contribute to heterogeneity in MOMP susceptibility. Our results show that stochastic effects strongly predispose sub-pools of fragmented mitochondria to MOMP under low apoptotic stress. At higher apoptotic stress, fractions of small mitochondria were more likely to escape MOMP than large mitochondria. Retrospective quantification of mitochondrial sizes in experimental scenarios of minority and majority MOMP confirmed these findings. We therefore conclude that stochasticity substantially contributes to enabling small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios and to escape MOMP in majority MOMP scenarios.

DOI: https://doi.org/10.1038/s41419-025-08258-9
Bioelectrochemistry. 2025 Dec 15. pii: S1567-5394(25)00304-4. [Epub ahead of print]169 109201

Ferutinin can form transient pores in lipid membranes in the presence of magnesium or calcium ions.

Zaret G Denieva, Alexander M Firsov, Ljudmila S Khailova, Sergey A Akimov, Elena A Kotova, Oleg V Batishchev, Yuri N Antonenko.

  The natural phytoestrogen ferutinin acts as a divalent cation-selective ionophore, promoting the opening of Ca2+-activated permeability transition pore (PTP) in mitochondria. Here, we found that Mg2+ cations, known to suppress PTP, markedly augmented the ferutinin-induced permeabilization of rat liver mitochondria. To uncover the permeabilization mechanism, we measured calcein flow from large (LUV) and giant (GUV) unilamellar vesicles. In both cases, the ferutinin-induced calcein efflux was significantly enhanced in the presence of Ca2+ or Mg2+. Calcein influx into GUV stopped within 15-min incubation with ferutinin and Ca2+. In electrophysiological experiments, ferutinin caused a smooth increase in the electrical current through planar bilayer lipid membranes (BLM) in the presence of Ca2+ or Mg2+, followed by burst of fluctuations in the current at its high level. In patch-clamp BLM experiments, we detected transient channel activity upon the addition of ferutinin together with Ca2+, diminishing over minutes time scale. We propose permeabilization mechanism which involves adsorption of ferutinin on lipid membranes, its dimerization upon binding Mg2+ or Ca2+, leading to mechanical stress induction, and ultimately to membrane pore formation. The mechanical stress is then gradually relieved due to translocation of ferutinin dimers and lipid molecules to the opposite lipid monolayer, resulting in pore closure.

Keywords:  Bilayer lipid membrane; Calcein leakage; Ferutinin; Giant liposomes; Large unilamellar vesicles; Mitochondria; Permeabilization

DOI:  https://doi.org/10.1016/j.bioelechem.2025.109201
J Pharm Anal. 2025 Nov;15(11): 101272

Mitochondrial membrane chromatography: Discovery of mitochondrial targeting modulators.

Wu Su, Yu Kong, Hua Li, Yongyao Wang, Lizhuo Wang, Le Shi, Huaizhen He, Shengli Han, Hui Guo, Jiankang Liu, Jiangang Long.

  Mitochondria are fundamental organelles that play a crucial role in cellular energy metabolism, substance metabolism, and various essential cellular signaling pathways. The dysfunction of mitochondria is significantly implicated in the onset and progression of aging, neurodegenerative diseases, metabolic disorders, and tumors, thereby rendering mitochondria-targeted regulation, a vital strategy for disease prevention and treatment. The recently developed mitochondrial membrane chromatography (MMC) technique, which immobilizes mitochondrial proteins as a chromatographic separation medium, has shown great potential for efficiently screening mitochondria-targeted modulators from complex compound library. In contrast to traditional screening methods, MMC has no need to purify mitochondrial proteins and can preserve its in situ and physiological conformation. Consequently, it presents broader application prospects for screening mitochondrial modulators as well as investigating receptor-ligand interactions involving any target protein associated with mitochondria. This review aims to elucidate the critical role of mitochondria in the development and progression of major chronic diseases, discuss recent advancements and applications of MMC, and propose future directions for MMC in the identification of novel mitochondrial modulators.

Keywords:  Major chronic diseases; Mitochondrial membrane chromatography; Mitochondrial modulators; Mitochondrial nutrients; Molecular screening

DOI:  https://doi.org/10.1016/j.jpha.2025.101272
Food Chem. 2025 Dec 09. pii: S0308-8146(25)04771-5. [Epub ahead of print]500 147519

Study on Smac promoting mitochondrial pathway apoptosis and muscle tenderization during postmortem aging of Tibetan sheep meat.

Jingyu Wang, Yang Liu, Tieying Hu, Han Wang, Zhaobin Guo, Aixia Li, Xixiong Shi.

  Postmortem aging is one of the valid methods for meat tenderization. After animal slaughter, muscle cells primarily undergo death in the form of apoptosis. Mitochondria are affected by postmortem stress conditions and initiate the mitochondrial pathway of apoptosis, which may contribute to meat tenderization. Smac is an apoptotic factor in the mitochondria, which can promote the degradation of inhibitor of apoptosis proteins (IAPs), thus activating caspases to induce apoptosis of tumor cells via the mitochondrial pathway. However, how Smac affects mitochondrial pathway apoptosis and muscle tenderization during postmortem aging of meat has not been reported. Thus, this study sought to elucidate the role of Smac in mitochondrial pathway apoptosis and muscle tenderization during postmortem aging of Tibetan sheep meat. Tibetan sheep meat was treated with 0.1 mmol/L GDC-0152 and aged at 4 °C. The related indicators were determined subsequently. Results demonstrated that the IAPs ubiquitin ligase activity, MPTP opening degree, caspase-9/3 activity, Apoptosis protease activating factor-1 (Apaf-1) concentration, apoptosis rate and MFI value of the GDC-0152 group were markedly elevated compared to the control group, while the mitochondrial membrane potential (MMP), cytoplasmic Cyt-c reduction level, IAPs concentration and shear force value were substantially decreased (P < 0.05). Furthermore, more nuclear chromatin condensation and cell shrinkage were observed in the GDC-0152 treatment group. In conclusion, Smac could promote the degradation of IAPs, accelerate mitochondrial damage, induce Cyt-c oxidation and Apaf-1 recruitment during postmortem aging of Tibetan sheep meat, thus activating caspase-9/3, facilitating mitochondrial pathway apoptosis and effectively improving Tibetan sheep meat tenderness.

Keywords:  Mitochondrial apoptotic pathway; Postmortem aging; Smac; Tenderization; Tibetan sheep meat

DOI:  https://doi.org/10.1016/j.foodchem.2025.147519
Cancer Res. 2025 Dec 15.

Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.

Lili Bao, Keying Li, Yue Fan, Zhen Ge, Yang Zeng, Tian Xia, Qicheng Zhang, Si Pan, Wenhui Chen, Haimeng Yin, Bo You.

Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we employed a 3D suspension culture model combined with proteomic screening, identifying a relationship between the dynamin-like protein Drp1 and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK-MFF-Drp1 and AMPK-mTOR-Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1-BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0622
PLoS One. 2025 ;20(12): e0338420

Comprehensive analysis of genes associated with necroptosis and pyroptosis in intestinal ischemia-reperfusion injury.

Shuang Bao, YanBo Sun, YiChen Hu, XueFen Lei, YuanPei Zhao, WeiMing Li.

BACKGROUND: Intestinal ischemia-reperfusion (II/R) injury is a severe clinical condition in which regulated cell death programs-including pyroptosis and necroptosis-have emerged as key drivers of tissue damage and inflammation. We sought to delineate cell-death-related molecular signatures and candidate therapeutic targets in II/R injury.
METHODS: We obtained transcriptome datasets from Gene Expression Omnibus (GEO) databases for mice (GSE96733, GSE232246) and humans (GSE37013). We cross-referenced genes associated with necroptosis and pyroptosis with differentially expressed genes to identify death-related features. Hub genes were identified through the topological structure of protein interaction networks and validated using an internal validation set, an independent validation set, WGCNA, and qRT-PCR. These genes were also associated with immune cell infiltration. Drug-gene interactions were predicted using DGIdb and verified through molecular docking.
RESULTS: We identified 1,027 differentially expressed genes (DEGs) in the training set and derived 7 cell death-related differentially expressed genes (DCDEGs) by intersecting gene sets associated with necroptosis and pyroptosis. PPI-based prioritization identified four hub genes-Il1β, Ripk3, Sting1 (Tmem173), and Tnfaip3-suggesting cross-regulatory interactions between inflammation and cell death in ischemia-reperfusion pathology. These hub genes were validated using WGCNA analysis and an internal validation set. Immune infiltration analysis indicated significant correlations between hub genes and multiple immune compartments. A predictive model showed good discrimination in the discovery data, and 54 candidate drugs targeting the hub genes were retrieved. qRT-PCR confirmed dysregulation of three hub genes.
CONCLUSION: Il1β, Ripk3, Sting1, and Tnaip3 were identified as hub genes associated with necroptosis and pyroptosis in intestinal ischemia-reperfusion (II/R) injury. This study provides a reproducible framework and identifies testable targets for translational exploration.

DOI: https://doi.org/10.1371/journal.pone.0338420
iScience. 2025 Dec 19. 28(12): 114052

MRPL37 promotes hepatocellular carcinoma progression through modulating mitochondrial energy metabolism.

Yigan Zhang, Minjie Chen, Huidi Li, Hao Deng, Shuwen Chen, Jiaxin Ni, Junjie Hu, Sixian Lei, Linsheng Huang, Shuangsuo Dang, Zhuoshun Yang, Wuhua Zhou, Deping Ding, Yanbin Dong, Zhongji Meng.

  Mitochondrial ribosomal proteins of the large subunit (MRPLs) are critical for mitochondrial function and cellular energy metabolism. However, the role of the MRPL family in hepatocellular carcinoma (HCC) remains poorly understood. Here, we leveraged The Cancer Genome Atlas (TCGA) liver cancer data to develop a subtype classification and prognostic model based on the MRPL family genes, identifying MRPL37 as a key gene associated with HCC progression. Clinically, MRPL37 upregulation is associated with HCC progression and poor prognosis. Functionally, MRPL37 knockdown significantly inhibits HCC cell proliferation, disrupts cell cycle progression, and induces apoptosis in vitro. In vivo, silencing MRPL37 reduces tumor growth in both xenograft and spontaneous liver cancer models. Mechanistically, MRPL37 regulates mitochondrial protein synthesis, influencing key metabolic pathways and mitochondrial function, including oxidative phosphorylation. Our results suggest MRPL37 as a critical regulator of energy metabolism in HCC, highlighting its potential as a therapeutic target for liver cancer.

Keywords:  cancer; human metabolism; organizational aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114052
Mol Biol Rep. 2025 Dec 18. 53(1): 208

The role and interplay among Autophagy, Apoptosis, and ferroptosis in acute pancreatitis: mechanisms and therapeutic approaches.

Islam Ahmed Abdelmawgood, Donia Mohamed Hussien, Michael Ibrahim Boushra.

  Acute pancreatitis (AP) is a prevalent gastrointestinal condition characterized by an inflammatory response in the pancreas, with a global prevalence of 4.9-73.4 per 100,000 individuals. As the disease advances, its severity and prognosis fluctuate. Mechanisms of programmed cell death (PCD) include apoptosis, ferroptosis, and autophagy; understanding their interactions is crucial for maintaining cellular homeostasis. Each pathway represents a distinct PCD process, and current studies emphasize the complex interrelationships and reciprocal effects among them. Therefore, investigating these interactions is essential for understanding how cells determine their fate and how these mechanisms contribute to various illnesses. Increasing evidence indicates that PCD significantly contributes to the development of AP, and drugs targeting various forms of PCD constitute a possible treatment approach. Consequently, understanding the function and mechanism of PCD in AP enhances our understanding of its pathophysiological mechanisms and offers substantial benefits for the management of AP. The review's importance lies in examining the interactions among ferroptosis, apoptosis, and autophagy, with critical implications for the development of therapeutic approaches, especially in conditions characterized by dysregulated cell death. By analyzing the biochemical interactions among these pathways, scientists may identify novel drug targets and develop strategies to regulate cell fate successfully. This review examines the interplay and crosstalk among apoptosis, autophagy, and ferroptosis signaling pathways in the regulation of AP development.

Keywords:  Acute pancreatitis; Apoptosis; Autophagy; Ferroptosis; Programmed cell death

DOI:  https://doi.org/10.1007/s11033-025-11319-z