bims-miptne 2026-05-17 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–05–17
ten papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.
Inhibition of mPTP and GSDME-mediated pyroptosis alleviates lung injury in septic mice.
Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.
Restoration of mitochondrial Ca2+ and redox homeostasis by enhancement of SK channels rescues Ca2+ cycling in HFpEF cardiomyocytes.
Terahertz Waves Trigger Apoptosis in Cutaneous Squamous Cell Carcinoma via Apoptosis-Inducing Factor Mediated Mitochondrial Pathway.
170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.
Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
Chronic quercetin supplementation modulates cardiac function and signaling pathways in aged male Wistar rat hearts subjected to ischemia-reperfusion.

Nat Metab. 2026 May 13.

MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.

Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.

Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.

DOI: https://doi.org/10.1038/s42255-026-01513-z
Pharmacol Res. 2026 May 07. pii: S1043-6618(26)00149-0. [Epub ahead of print]229 108234

Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.

Emanuela Franchini, Matteo Bulloni, Anna Sorgente, Katarina Paulikova, Laura Cassina, Ilaria Marafelli, Irene Sambri, Linda Pattini, Giorgio Casari.

  The mitochondrial permeability transition pore (mPTP) is a voltage‑ and calcium‑regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from SPG7 patient cells and healthy control confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.

Keywords:  Berberine; Hereditary spastic paraplegia; High content screening; MPTP; Mitochondrial permeability transition pore; SPG7

DOI:  https://doi.org/10.1016/j.phrs.2026.108234
Eur J Pharmacol. 2026 May 13. pii: S0014-2999(26)00449-8. [Epub ahead of print] 178967

Inhibition of mPTP and GSDME-mediated pyroptosis alleviates lung injury in septic mice.

Na Lu, Meng-Jie Yu, Rui Zhang, Zhao-Fei Meng, Hong-Wei Ye, Ying Yu, Qin Gao, Jun-Feng Hu.

   OBJECTIVE: To explore the role of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) - mediated pyroptosis in septic lung injury in mice model.
METHODS: Adult male c57BL / 6J mice were randomly assigned with 10 mice in each group. Sepsis model was established by cecal ligation and puncture (CLP) operation. Alisporivir (AL) was used to inhibit the opening of mPTP, plumbagin (PL) was used to open mPTP. Knockdown or overexpression of GSDME were done by Adeno associated virus 6 (AAV 6). The changes of lung tissue, ultrastructure, reactive oxygen species (ROS), GSDME-mediated pyroptosis related proteins, inflammatory factors and mitochondrial function were detected.
RESULTS: Compared with Sham group, the aggravating of lung injury, mitochondrial dysfunction, oxidative stress and inflammatory reaction were shown in CLP and GSDME high-expression groups, and the opening of mPTP, the mRNA levels of pyroptosis related genes were increased, the expressions of pyroptosis related proteins were increased. After inhibiting mPTP opening by AL or knockdown GSDME respectively, septic lung injury was alleviated, mitochondrial function was improved, oxidative stress and inflammatory response were reduced, the mRNA levels of GSDME and Caspase-3 were decreased, the protein expressions of GSDME, Caspase-3, IL-1β and IL-18 were reduced. In knockdown GSDME group, the application of PL to open mPTP still played the protective role.
CONCLUSION: Inhibiting mPTP opening or GSDME-mediated pyroptosis both alleviated septic lung injury. The mPTP is the upstream of GSDME, GSDME-N can also positively promote mPTP opening, mPTP and GSDME regulates each other in the GSDME-mediated pyroptosis pathway.

Keywords:  GSDME; Septic lung injury; mitochondrial permeability transition pore; pyroptosis

DOI:  https://doi.org/10.1016/j.ejphar.2026.178967
Mol Cells. 2026 May 13. pii: S1016-8478(26)00060-9. [Epub ahead of print] 100369

Small Molecule Inhibition of VDAC1 Reroutes Mitochondrial Metabolite Flux.

Seyed Majed Modaresi, Leilei Zhang, Amir Ata Saei, Morris Degen, Mohammad Khavani, Hassan Gharibi, Ákos Végvári, Zhiwei Ye, Jie Zhang, Evgeny Pavlov, Elizabeth A Jonas, Kenneth D Tew, Sebastian Hiller, Danyelle M Townsend, Eduardo N Maldonado.

  Voltage dependent anion channels (VDACs 1, 2 and 3) in the outer mitochondrial membrane control the flux of anions and oxidizable substrates that sustain mitochondrial metabolism. NADH closes VDAC by binding to a pocket, conserved in all isoforms, located in the inner wall of the channel. Previously, we identified the small molecule SC18 that targets the NADH-binding pocket of VDAC1 employing computational analysis. Here, we explored the interaction between SC18 and VDAC1 using High-resolution Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. Atomically resolved data precisely confirmed the computational results, showing that SC18 binds to a site on VDAC1 that partially overlaps with the NADH binding pocket. SC18, in the presence of NADH blocked the conductance of VDAC1 reconstituted in lipid bilayers. To determine the metabolic effect of SC18, we combined readouts of mitochondrial metabolism and glycolysis with functional metabolomics and proteomics. Short-term treatment with SC18 inhibited mitochondrial metabolism and ATP production. Treatment over 24 h and 48 h further reduced mitochondrial uptake of pyruvate and glutamine, utilization of tricarboxylic acid cycle intermediates, as well as lipid, DNA and amino acid synthesis. Concomitant with the inhibition of mitochondrial metabolism, cellular uptake of glucose and glutamine increased in parallel with augmented lactate release. These results indicate that compensatory enhanced glycolysis sustains ATP production after impaired mitochondrial function induced by SC18 blockage of VDAC1. Our work set a mechanistic foundation for VDAC1 inhibition as a novel strategy to target and reprogram cancer metabolism through modulation of the biosynthetic ability of mitochondria.

Keywords:  SC18; VDAC1; cancer metabolism; glycolysis; mitochondria

DOI:  https://doi.org/10.1016/j.mocell.2026.100369
J Mol Cell Cardiol. 2026 May 08. pii: S0022-2828(26)00063-5. [Epub ahead of print]216 1-12

Restoration of mitochondrial Ca2+ and redox homeostasis by enhancement of SK channels rescues Ca2+ cycling in HFpEF cardiomyocytes.

Shanna Hamilton, Radmila Terentyeva, Roland Veress, Fruzsina Perger, Veronica Loyo, Matthew W Gorr, Joseph Owusu-Sarfo, Sage Quiggle, Sandor Gyorke, Daniel Scherr, Richard T Clements, Senka Ljubojevic-Holzer, Przemysław B Radwański, Harpreet Singh, Dmitry Terentyev, Andriy E Belevych.

  Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases. In addition to diastolic dysfunction, patients with HFpEF have a substantial risk of sudden cardiac death, suggesting a potential contribution of malignant ventricular arrhythmias. Recently, small conductance Ca2+-activated K+ (SK) channels have emerged as potential modulators of mitochondria-dependent production of harmful reactive oxygen species (ROS). This study aimed to evaluate SK channel enhancement as a novel strategy to reverse proarrhythmic changes in intracellular Ca2+ cycling and in mitochondrial redox and Ca2+ homeostasis in ventricular myocytes using obese ZSF1 rat model of HFpEF. Confocal imaging of Ca2+ and ROS was performed in ventricular myocytes isolated from lean and obese ZSF1 rats. Mitochondrial matrix Ca2+ and ROS levels were measured using matrix-targeted biosensors mtRCamp1h and MLS-HyPer7, respectively. SK channel activity was enhanced by adenoviral overexpression of rat SK channel type 2 and by pharmacological activators NS309 and Riluzole. Ventricular myocytes from obese ZSF1 rats, when periodically paced and exposed to the β-adrenergic agonist isoproterenol, showed increased pro-arrhythmic diastolic sarcoplasmic reticulum (SR) Ca2+ release, elevated mitochondrial ROS production, and marked mitochondrial Ca2+ overload. SK channel enhancement prevented mitochondrial Ca2+ overload, reduced ROS emission, and improved cytosolic Ca2+ cycling by suppressing diastolic SR Ca2+ release These findings identify SK channel activation as a potential antiarrhythmic therapeutic strategy in HFpEF by limiting mitochondrial Ca2+ uptake, reducing oxidative stress and stabilizing intracellular Ca2+ dynamics.

Keywords:  Calcium handling; HFpEF; Mitochondria; Ryanodine receptor; SK channels

DOI:  https://doi.org/10.1016/j.yjmcc.2026.05.004
Cells. 2026 Apr 29. pii: 810. [Epub ahead of print]15(9):

Terahertz Waves Trigger Apoptosis in Cutaneous Squamous Cell Carcinoma via Apoptosis-Inducing Factor Mediated Mitochondrial Pathway.

Liu Sun, Wenxia Wang, Shuocheng She, Lei Wang, Jinwu Zhao, Pandeng Hou, Mingxia He.

   BACKGROUND: Terahertz (THz) waves exhibit both photon-like and electron-like properties, showing emerging potential in biomedical applications. Cutaneous squamous cell carcinoma (CSCC) is one of the most common skin tumors. Studies have reported that THz waves can induce apoptosis in cancer cells or ablate tumor tissues. Our previous studies also confirmed that 0.1 THz radiation could significantly promote apoptosis in cutaneous melanoma cells, while it had no apparent effect on fibroblast viability, proliferation, migration, and apoptosis. However, the effects of 0.1 THz radiation on CSCC cells have not yet been explored. Furthermore, there remains a lack of investigation into the structural and functional effects on fibroblasts. Therefore, it is necessary to conduct a systematic study to evaluate the influence of 0.1 THz radiation on both CSCC cells and fibroblasts in order to better understand its potential therapeutic applications in the treatment of skin cancer.
PURPOSE: This study aims to explore the biological effects of 0.1 THz radiation on SCC-7 cells and to uncover the molecular mechanisms underlying THz-induced apoptosis, as well as its potential effect on L-929 cells.
METHODS: Cell viability was evaluated through the CCK-8 assay, while cell cycle distribution was analyzed with the DNA content detection kit. Wound healing assays were performed to assess cell migration, and Annexin V-FITC staining was used to detect apoptosis. Caspase-3 activity was measured using the caspase-3 activity assay kit. Cell morphology was observed using the Atomic Force Microscope (AFM) and the Transmission Electron Microscopy (TEM). Alterations in membrane potential were detected with the M09 membrane potential probe kit, and intracellular Ca2+ levels were quantified using the Fluo-8 AM fluorescent probe. Mitochondrial permeability transition pore (mPTP) opening was assessed with the MPTP detection kit, mitochondrial membrane potential changes were measured using the JC-1 probe kit, and cellular ATP levels were measured with the enhanced ATP assay kit. Subsequently, proteomic analysis was performed. Intracellular reactive oxygen species (ROS) levels were quantified with the ROS detection kit, and cytochrome c (Cyt c) release was quantified using the mouse Cyt c ELISA kit. Apoptosis-inducing factor (AIF) expression was analyzed at both mRNA and protein levels by quantitative real-time PCR (qPCR) and Western blot. AIF expression in CSCC tissues was further evaluated based on the GSE42677 and GSE45164 databases. Finally, cyclosporin A (CsA) was used to inhibit mPTP, and in combination with the iMAC inhibitor, the Aifm1 expression and Cyt c release were examined.
RESULTS: Our results showed that THz waves significantly disrupted the membrane integrity of SCC-7 cells and induced mitochondrial structural and functional damage. This resulted in a significant increase in ROS levels and the activation of mPTP and the mitochondrial apoptosis channel (MAC). THz radiation promoted the release of Cyt c and AIF from mitochondria, triggering a noncanonical caspase-3-dependent apoptosis pathway. Notably, L-929 cells did not show significant phenotypic or apoptotic changes under the same irradiation conditions. Bioinformatics analysis of the Gene Expression Omnibus (GEO) database revealed that AIF expression was significantly altered in CSCC tissues compared to normal skin tissues.
CONCLUSIONS: These findings indicated that 0.1 THz radiation effectively induced apoptosis in SCC-7 cells by triggering mitochondrial dysfunction and ROS generation, which led to the release of AIF. Furthermore, the dysregulation of AIF in CSCC tissues suggested its potential as a promising biomarker. These results provided important molecular insights into the therapeutic potential of THz radiation, particularly for the treatment of cutaneous squamous cell carcinoma.

Keywords:  0.1 THz radiation; SCC-7 cells; apoptosis-inducing factor; cytochrome c; mitochondrial pathway

DOI:  https://doi.org/10.3390/cells15090810
J Clin Pharmacol. 2026 May;66(5): e70209

170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.

Volkmar Weissig.

  One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.

Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.1002/jcph.70209
Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2527963123

Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: A case study with Bid.

Christina Elsner, Anton Hanke, Oscar Vadas, Francesco Luigi Gervasio, Enrica Bordignon.

  Intrinsic apoptosis is a form of cell death which is activated, executed, and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structural model of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing interresidue distances and dynamic solvent accessibilities complemented by integrative modeling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBid's C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis.

Keywords:  Bcl-2 proteins; DEER; MD simulations; apoptosis; mitochondria

DOI:  https://doi.org/10.1073/pnas.2527963123
Nat Commun. 2026 May 12.

Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.

Linghui Kong, Jiajian Liang, Dan Liu, Shanshan Jia, Hui Gu, Yiwen He, Wenting Luo, Songying Cao, Yizhang Dong, Chao Yang, Minghui Liao, Guojia Wan, Bo Du, Dongxue Ding, Wei Ma, Xiaowei Wei, Anhua Wu, Zhengwei Yuan.

Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-13C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.

DOI: https://doi.org/10.1038/s41467-026-72988-3
Front Cardiovasc Med. 2026 ;13 1745113

Chronic quercetin supplementation modulates cardiac function and signaling pathways in aged male Wistar rat hearts subjected to ischemia-reperfusion.

Jakub Strapec, Lucia Kindernay, Eva Kralova, Katarina Krsteva, Peter Pokreisz, Monika Bartekova, Tomas Rajtik, Kristina Ferenczyova.

   Objectives: Quercetin (QCT), a natural polyphenol with antioxidant, anti-inflammatory, and antithrombotic properties, has shown cardioprotective effects in various in vitro and in vivo models of myocardial ischemia/reperfusion (I/R) injury. However, these effects have predominantly been demonstrated in young, healthy animals, which limit their translational potential, as patients with ischemic heart disease are typically middle-aged or older and frequently present with comorbidities. The present study aimed to evaluate the cardioprotective potential of chronic QCT treatment in aged rats.
Methods: Male Wistar rats (20 months old at arrival) received QCT orally (20 mg/kg/day) for 6 weeks. After treatment, rats were euthanized and isolated hearts were perfused according to Langendorff, subjected to 30 min of global ischemia and 120 min of reperfusion. Cardiac function recovery was monitored during the first 40 min of reperfusion by assessment of electrical and mechanical parameters. Infarct size was determined by TTC staining at the end of reperfusion. In parallel groups, left ventricular tissue was collected immediately after treatment for Western blot (WB) analysis of regulatory proteins.
Results: QCT administration improved electrical function, mainly by reducing QT and QTc intervals during reperfusion compared with controls. In contrast, QCT did not improve recovery of contractile function, and it did not reduce infarct size. WB analysis revealed a significantly increased Bcl-2/Bax ratio, suggesting attenuated apoptosis, while expression of other apoptotic and autophagy-related proteins remained unaffected.
Conclusions: Compared with juvenile rat hearts, chronic QCT treatment exerts modest cardioprotective effects in aged hearts, characterized by improved electrical recovery and reduced pro-apoptotic signaling, independent of Reperfusion Injury Salvage Kinase (RISK) pathway or autophagy activation.

Keywords:  aging; apoptosis; autophagy; ischemia-reperfusion; quercetin

DOI:  https://doi.org/10.3389/fcvm.2026.1745113