bims-miptne 2026-02-08 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–02–08
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.
Reducing mitochondrial dysfunction through combination therapy to limit ischemia-reperfusion injury in male DCD rats.
SIRT3 attenuates chronic pain-induced depressive-like behaviors by deacetylating CypD at lysine 166 in central amygdala.
Dioclea violacea Lectin Preserves Brain Mitochondrial Function and Prevents Oxidative Damage after Ischemia/Reperfusion.
Honokiol blocks tumor development and metastasis through mitochondrion-targeted effects.
Targeting the Pyroptosis-Mitochondrial Homeostasis Crosstalk: Astaxanthin Attenuates Alcohol-Induced Inflammatory Liver Injury via Inhibition of cGAS-STING Signaling.
Recovery from apoptosis in photoreceptor cells: A role for mitophagy.
Functional specialization of Ca2+-binding motifs in human MICU1.
Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.

bioRxiv. 2026 Jan 19. pii: 2026.01.15.699680. [Epub ahead of print]

Phosphorylation of Cyclophilin-D is Not Required for Regulation of The Mitochondrial Permeability Transition Pore by GSK3β.

Linda Alex, Paula J Klutho, Lihui Song, Manuel Gutiérrez-Aguilar, Christopher P Baines.

Genetic inhibition of cyclophilin D (CypD) delays the opening of the mitochondrial permeability transition pore (MPTP) and therefore reduces necrotic cell death. Elucidation of factors that impact CypD activity is therefore key to understanding the regulation of MPTP opening. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine kinase that has been shown to modulate MPTP and cell death, potentially through phosphorylation of CypD. Therefore, we hypothesized that the mitochondrial fraction of GSK3β directly phosphorylates CypD and promotes opening of MPTP. Overexpression of full length GSK3β in mouse embryonic fibroblasts sensitized the MPTP and exacerbated oxidative stress-induced necrosis. In contrast, genetic inhibition of GSK3β protected against oxidant-induced cytotoxicity but did not affect the MPTP. Recombinant GSK3β could directly bind to and phosphorylate recombinant CypD. Mass spectrometry revealed several putative GSK3β phosphorylation sites on CypD. However, mutation of these sites did not affect the peptidyl prolyl isomerase activity of CypD and reconstitution of these phosphomutants in CypD-deficient cells increased MPTP sensitivity and oxidative-induced cell death to the same extent as wild-type CypD. Further, targeted overexpression of either wild-type or kinase-inactive GSK3β in the mitochondrial matrix did not impact MPTP or cell death. Moreover, while proteinase-K digestion of cardiac mitochondria showed a significant amount of GSK3β in the mitochondria, it was not localized to the matrix. Finally, overexpression of GSK3β was still able to increase MPTP sensitivity and oxidative stress-induced death in CypD-null cells. Taken together, these data indicate that, while GSK3β can modulate MPTP, this appears to be independent of GSK3β's interaction with, or phosphorylation of CypD.

DOI: https://doi.org/10.64898/2026.01.15.699680
Front Cardiovasc Med. 2025 ;12 1625385

Reducing mitochondrial dysfunction through combination therapy to limit ischemia-reperfusion injury in male DCD rats.

Zachary Kiernan, Gina Labate, Qun Chen, Mohammed Quader.

   Introduction: Two predominant pathways contribute to ischemia reperfusion injury (IRI) following donation after circulatory death (DCD): mitochondrial permeability transition pore (MPTP) opening and Calpain-1 (CPN1) activation. Each pathway has established inhibitors; Cyclosporine A (CyA) and MDL-28170 (MDL), respectively, which are effective in modulating IRI in a DCD heart with 25 min of warm ischemia time (WIT). We studied the effect of co-administering CyA and MDL during reperfusion on infarct size and graft function in DCD rat hearts with extended WIT of 35 min.
Methods: Male rats were exposed to 35 min of warm ischemia followed by 90 min of reperfusion. During reperfusion, hearts were given either 0.5 mM of CyA, 10 mM of MDL, or mixed CyA and MDL. Cardiac function and coronary flow rates were monitored throughout reperfusion and infarct size at the end of reperfusion.
Results: Infarct size in hearts treated with mixed CyA + MDL (31.59 ± 7.1%) was less than that of MDL-treated hearts (33.26 ± 4.3%) but larger than CyA-treated hearts (25.49 ± 5.9%). Graft function and coronary flow rates were variable amongst groups. CyA-treated hearts had more profound infarct size reduction when compared to MDL, and no additional synergistic effect was seen with combination treatment.
Discussion: Our results indicate that MPTP opening contributes significantly to the development of IRI in DCD hearts.

Keywords:  MDL-28170; MPTP; cyclosporine A; donation after circulatory death; heart failure

DOI:  https://doi.org/10.3389/fcvm.2025.1625385
Eur J Pharmacol. 2026 Feb 03. pii: S0014-2999(26)00120-2. [Epub ahead of print] 178638

SIRT3 attenuates chronic pain-induced depressive-like behaviors by deacetylating CypD at lysine 166 in central amygdala.

Xiaobao Ding, Jinfeng Huang, Yiqi Liu, Wenli Hu, Yuwen Lin, Mengyuan Zhou, Xinyu Li, Yaolong Zhuang, Yuqing Wu, Chenghua Zhou.

  Chronic pain often acts as a trigger of depression. Mitochondrial dysfunction is increasingly recognized as a key player in the pathogenesis of depression and pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, has been found to ameliorate mitochondrial function. However, the role of SIRT3 in the development of chronic pain-induced depression remains unclear. In this study, it was observed that the expression of SIRT3 in the central amygdala (CeA) was downregulated in spared nerve injury (SNI) male mice with comorbid pain and depression. However, the overexpression of SIRT3 in CeA γ-aminobutyric acid-ergic (GABAergic) neurons mitigated the sensory pain and depressive-like behaviors induced by SNI. Further study demonstrated that the overexpression of SIRT3 in CeA GABAergic neurons decreased the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), inhibited the opening of mitochondrial permeability transition pore (mPTP) and the production of reactive oxygen species (ROS), and increased mitochondrial membrane potential (MMP) and manganese superoxide dismutase (MnSOD) levels in SNI mice. Nevertheless, CypD-K166R mutant mice that mimic deacetylation were protected from mitochondrial dysfunction and depressive-like behaviors caused by SNI. Furthermore, blocking mPTP opening using cyclosporin A (CsA) improved mitochondrial function and alleviated neuropathic pain and its comorbid depression in SNI mice. Taken together, our findings suggest that SIRT3 in CeA GABAergic neurons attenuates chronic pain and its comorbid depression by deacetylating CypD-K166 and subsequently ameliorating mitochondrial dysfunction. This study provides a potential therapeutic target for both the sensory and emotional dimensions of chronic pain.

Keywords:  CypD; SIRT3; central amygdala; depression; neuropathic pain

DOI:  https://doi.org/10.1016/j.ejphar.2026.178638
Biochimie. 2026 Feb 03. pii: S0300-9084(26)00026-X. [Epub ahead of print]

Dioclea violacea Lectin Preserves Brain Mitochondrial Function and Prevents Oxidative Damage after Ischemia/Reperfusion.

Pedro Lourenzo Oliveira Cunha, Maria Stella Batista de Freitas Neta, Ludmila Araújo de Lima, Iri Sandro Pampolha Lima, Renato Rodrigues Roma, Diógenes G da S Fernandes, Wanius Garcia, Claudener Souza Teixeira, Maria Elizabeth Pereira Nobre, Heberty Tarso Facundo.

  Ischemic brain damage is characterized by mitochondrial dysfunction and oxidative stress. Mitochondrial reactive oxygen species induce cellular damage during reperfusion. Dysregulated mitochondrial calcium influx triggers the opening of the mitochondrial permeability transition pore (MPTP), disrupting mitochondrial function and causing cell death. Dioclea violacea lectin (DVL) is a plant lectin which exhibits a diverse range of biological activities. Here, we aimed to investigate and characterize the effects of in vivo treatment with DVL in a rat model of ischemic stroke. DVL (0.5 μg) or saline were administrated by stereotaxic intracerebroventricular injection (volume of 1 μl) 15 mins prior to ischemia. Global cerebral ischemia was induced by bilateral carotid occlusion for 30 min. After 24 hours reperfusion we evaluated locomotor activity, oxidative stress markers (nitrite, thiobarbituric acid reactive substances - TBARS, mitochondrial H2O2 levels, and superoxide dismutase (SOD) activity), mitochondrial oxygen consumption and ADP/O (using a clark-type electrode). MPTP opening was determined by Ca2+-induced swelling. DVL (prior to ischemia) induced neuroprotective effects in rats` cerebral tissue. It restored the rats` exploratory behavior and mitigated depression. DVL-treated rats had improved brain mitochondrial oxygen consumption rates and ADP/O ratio. Additionally, DVL reduced oxidative stress (mitochondrial H2O2 production, TBARS, and nitrate levels) and preserved SOD activity. Finally, mitochondria isolated from DVL-treated rats had lower susceptibility to Ca2+-induced MPTP opening. Mechanistically, we found that DVL binds glutamate - an excitotoxic neurotransmitter highly released after ischemic insults. This study reveals a novel neuroprotective mechanism of a plant-derived lectin acting through mitochondrial preservation and oxidative stress reduction.

Keywords:  Free radicals; Ischemia/reperfusion; Lectin; Mitochondria; Neuroprotection

DOI:  https://doi.org/10.1016/j.biochi.2026.01.017
Cell Death Dis. 2026 Jan 30. 17(1): 186

Honokiol blocks tumor development and metastasis through mitochondrion-targeted effects.

Martina Grandi, Francesco Boldrin, Giovanni Risato, Silvia Grillini, Natascia Tiso, Francesco Argenton, Emanuela Leonardi, Silvio Tosatto, Giancarlo Solaini, Alessandra Baracca, Valentina Giorgio.

IF1 is the natural inhibitor of the mitochondrial ATP synthase during hydrolytic activity. It has been found to be overexpressed in many tumors, where it acts as a pro-oncogenic protein. During oxidative phosphorylation, IF1 binds to a novel site on the OSCP subunit of ATP synthase and promotes tumorigenesis by protecting cancer cells from permeability transition pore (PTP)-dependent apoptosis. In this work, honokiol, a biphenolic compound, showed binding affinity for two sites on the OSCP subunit, as predicted by molecular docking analysis. It was shown to be effective in disrupting the IF1-OSCP interaction and sensitizing cancer cells to apoptosis. In vivo, xenografts of zebrafish injected with IF1-expressing HeLa cells showed tumor development. The same xenografts, treated with honokiol, showed a significant reduction in tumor mass, similar to untreated fish injected with IF1 KO HeLa cells. In vitro, honokiol inhibits colony formation in soft agar of IF1-expressing HeLa cells by promoting the PTP opening and cell death, without any effect on cell proliferation. Interestingly, honokiol was shown to block metastasis in fish xenografts and migration in a wound healing assay, by promoting mitochondrial swelling in both control and IF1 KO cell lines, when cells are moving to close the scratch area. In conclusion, honokiol appears to be a promising anti-cancer compound, with pro-apoptotic properties through the displacement of IF1 from the OSCP subunit of ATP synthase, and anti-metastatic effects that are due to mitochondrial PTP opening.

DOI: https://doi.org/10.1038/s41419-026-08441-6
J Agric Food Chem. 2026 Feb 06.

Targeting the Pyroptosis-Mitochondrial Homeostasis Crosstalk: Astaxanthin Attenuates Alcohol-Induced Inflammatory Liver Injury via Inhibition of cGAS-STING Signaling.

Shousheng Liu, Haiping Zhang, Ronghuan Du, Xi Gao, Tianren Wang, Wenping Qin, Dan Sun, Hui Liang, Peng Wang.

  Emerging research evidence has established the critical role of inflammatory cascades in the development and progression of alcoholic liver injury with hepatocellular death serving as a principal driver. Notably, the dysregulated interplay between mitochondrial homeostasis and pyroptosis is primarily responsible for the alcohol-induced aberrant liver immune microenvironment, characterized by nonresolving inflammation. Given the considerable limitations in the current treatment for alcoholic steatohepatitis (ASH), it is imperative to explore targeted nutritional interventions as alternative therapies. Here, we established an ASH model with C57BL/6J mice and demonstrated that astaxanthin (AST) administration significantly protected against alcohol-induced inflammatory liver injury through dual mechanisms: 1) suppression of hepatocyte pyroptosis by inhibiting the NLRP-3/Caspase/GSDMD signaling axis and 2) mitigation of mitochondrial dysfunction evidenced by structural membrane integrity restoration and redox homeostasis rebalancing. Mechanistically, AST intervention impeded the cytoplasmic translocation of mitochondrial DNA (mtDNA), thereby concurrently inhibiting AIM2 inflammasome activation and cGAS/STING signaling. In vitro studies further confirmed dose-dependent attenuation of alcohol-induced hepatotoxicity by AST, marked by reduced pyroptotic cell death and diminished proinflammatory cytokine secretion (IL-1β, IL-18). Mitochondrial protection was further evidenced through restored membrane potential (ΔΨm), decreased cytoplasmic Cytochrome C release, and attenuated mtDNA leakage. Moreover, we identified a novel molecular interaction, wherein AST competitively binds lipid-binding motifs within the β1-β2 loop of the GSDMD-N-terminal domain, potentially interfering with pyroptotic pore formation. Further overexpression experiments confirmed the improvement effect of AST on pyroptosis induced by GSDMD-N pore formation. Concurrently, AST exhibited potent antioxidant effects against alcohol-induced cardiolipin peroxidation, suggesting dual therapeutic modalities targeting both pyroptotic execution and mitochondrial membrane stabilization. Collectively, our findings identify AST as a promising candidate for therapeutic interventions against alcoholic inflammatory liver injury through coordinated modulation of the pyroptosis-mitochondrial homeostasis crosstalk, offering novel insights into nutritional intervention strategies for alcohol-related liver pathologies.

Keywords:  alcoholic steatohepatitis; astaxanthin; cGAS/STING; mitochondrial dysfunction; pyroptosis

DOI:  https://doi.org/10.1021/acs.jafc.5c12678
Cell Death Dis. 2026 Jan 30. 17(1): 167

Recovery from apoptosis in photoreceptor cells: A role for mitophagy.

Bhavneet Kaur, Bruna Miglioranza Scavuzzi, Jingyu Yao, Mengling Yang, Lin Jia, Stephen I Lentz, Jaya Sadda, Andrew J Kocab, Sumathi Shanmugam, David N Zacks.

Photoreceptors (PRs) are specialized light-sensitive cells responsible for vision, and their death is the primary cause of retinal degeneration and vision loss. Recent studies using cells such as HeLa and PC12 have demonstrated cellular recovery even from late stages of apoptosis. Here, we demonstrate for the first time that PR cells can recover from features of apoptosis following exposure to apoptotic stressors. Upon apoptotic stimuli (staurosporine or hypoxia), 661 W cells, a murine cone PR cell line, exhibited morphological and functional features of apoptosis, such as rounding and blebbing, caspase-3 activation, PARP cleavage, and phosphatidylserine externalization. These processes were reversed upon the alleviation of stress. We also observed that mitochondrial function is central to apoptotic recovery of photoreceptor cells, as evidenced by the restoration of intracellular ATP levels and reduction in mitochondrial reactive oxygen species (mROS). Mitophagy was demonstrated to play a crucial role in cell survival, with increased protein and mRNA expression of mitophagy markers during recovery from apoptosis. Furthermore, the modulation of mitophagy confirmed its protective role in the recovery phase, as its induction with MF-094 reduced apoptosis while its inhibition with Mdivi-1 exacerbated cell death. In vivo, we demonstrate the recovery of PRs from apoptosis using an experimental model of transient retinal detachment. Altogether, the findings of this study indicate that PR cells can recover from entry into the apoptotic cascade, and that mitophagy is essential for apoptotic recovery in these cells.

DOI: https://doi.org/10.1038/s41419-026-08436-3
Int J Biol Macromol. 2026 Feb 03. pii: S0141-8130(26)00628-8. [Epub ahead of print]346 150702

Functional specialization of Ca2+-binding motifs in human MICU1.

Leandro Matías Sommese, Nicolás Palopoli, Maria Silvina Fornasari, Gustavo Parisi, Toni Gabaldón, Ana Julia Velez Rueda.

  The mitochondrial Ca2+ uniporter (mtMCU) channel is essential for energy production, cytosolic Ca2+ signaling, and cell death regulation. Calcium dependent proteins MICU1 and MICU2 regulate its activity. To date, twelve MICU1 structures have been experimentally determined. In each, about 30% of the residues are missing, excluding key disordered regions and limiting a complete molecular-level description of the Ca2+-sensing mechanism. Using structural modeling, molecular dynamics simulations, large-scale sequence analysis, and in silico mutagenesis, we investigate MICU1's Ca2+-binding sites from both conformational and evolutionary perspectives. We identified a previously uncharacterized pseudo-EF-hand (pEF-h) motif that acts as an early Ca2+ sensor, triggering structural transitions that prime the canonical EF-h1 and EF-h2 sites for subsequent binding. Occupation of the pEF-h induces coordinated changes in surface charge distribution, a decrease in isoelectric point, and enhanced flexibility of the EF-hand regions, facilitating high-affinity Ca2+ binding. In addition, in silico single and double mutagenesis targeting the pEF-h, EF-h1, and EF-h2 demonstrated that mutations at the pEF-h markedly reduced Ca2+ occupancy and delayed conformational transitions. Evolutionary analysis highlighted the relevance of the EF-hand motifs, supported by the evolutionary shaping of MICU1 EF-hand motifs across major eukaryotic lineages using clustering analysis, and revealed strong lineage-specific segregation. We observed patterns suggesting that high-affinity Ca2+ binding evolved in parallel with increasing regulatory complexity in metazoans. Together, these findings provide a unified structural and evolutionary framework explaining how MICU1 functions as a Ca2+-dependent molecular switch that sets the threshold and precision of mitochondrial Ca2+ uptake through a hierarchical and cooperative activation mechanism.

Keywords:  Ca(2+) uniporter; Conformational diversity; EF-hand motif's structural and evolutionary constraints; In silico mutagenesis; MICU1; Structural dynamics

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150702
Sci Adv. 2026 Jan 30. 12(5): eaec5092

Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.

Jeff J Subleski, Erika M Palmieri, Jessica F Walls, Steven Hsu, Ian A Bettencourt, Timothy R Gower, Scott K Durum, Daniel W McVicar.

Glycolysis is an essential metabolic pathway for rapidly expanding T cells, but the role of pyruvate kinase muscle 1 (PKM1) and PKM2 in regulating this process is underappreciated. Here, using a pharmacological activator and targeted deletion of PKM2 in T cells, we delineated distinct functions of PKM1 and PKM2 in regulating CD4 T cell survival during homeostasis and expansion. Expanding PKM2-deficient CD4 T cells increased PKM1 expression with associated mitochondrial reactive oxygen species-mediated cell death. Examination of T cell compartments revealed that PKM2-deficient CD4 T cells were unaltered in the thymus but were significantly reduced in peripheral tissues as mice aged. The inability of PKM1 to protect CD4 T cells in the absence of PKM2 led to less severe T cell-mediated colitis as PKM2-deficient pathogenic cells were significantly reduced compared with control cells. This study shows that PKM2 is critical for CD4 T cell survival during expansion and homeostasis.

DOI: https://doi.org/10.1126/sciadv.aec5092