bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2026–05–31
eight papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
  2. Mitofilin Preservation Mitigates Cardiac Injury in Donation-After-Circulatory-Death Hearts.
  3. Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.
  4. Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
  5. Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
  6. Mitochondrial Calcium Overload Drives mtDNA-cGAS-STING Activation via VDAC1 and MCU Upregulation in Periodontitis.
  7. A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.
  8. Ethylmalonic and Methylsuccinic Acids Disrupt Bioenergetics and Induce Mitochondrial Permeability Transition Through Thiol Redox Modulation in Rat Striatum: Potential Mechanisms Involved in Ethylmalonic Encephalopathy.
  1. Cell Death Differ. 2026 May 27.
    Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
    Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.
      Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-026-01769-8
  2. Cells. 2026 May 18. pii: 920. [Epub ahead of print]15(10):
    Mitofilin Preservation Mitigates Cardiac Injury in Donation-After-Circulatory-Death Hearts.
    Qun Chen, Zachary Kiernan, Gina Labate, Oluwatoyin Akande, Edward J Lesnefsky, Mohammed Quader.
      Donation after circulatory death (DCD) involves unavoidable ischemia-reperfusion injury (IRI). Mitochondrial permeability transition pore (MPTP) opening plays a critical role in DCD heart injury. Activation of ubiquitous calpains, including calpain-1 and calpain-2 (CPN1/2), increases MPTP opening in DCD hearts. Mitofilin, a mitochondrial inner membrane protein that regulates cristae morphology, is also involved in MPTP opening during ischemia-reperfusion. However, it remains unclear whether CPN1/2 activation contributes to mitofilin-mediated IRI in DCD hearts. We first incubated a mitofilin peptide with exogenous CPN1 in vitro to investigate the link between CPN1 activation and mitofilin degradation. Next, we tested whether CPN1/2 inhibition reduces cardiac injury in DCD hearts by preserving mitofilin and limiting MPTP opening. Sprague-Dawley (SD) rat hearts were subjected to 25 min of in vivo ischemia followed by ex vivo perfusion with or without the CPN1/2 inhibitor MDL-28170 (10 µM). In vitro incubation with CPN1 led to mitofilin degradation, confirming mitofilin as a CPN1 substrate. CPN1/2 inhibition significantly reduced infarct size compared with untreated DCD hearts, preserved mitofilin expression, and decreased MPTP opening. These findings indicate that CPN1/2 activation promotes MPTP opening in DCD hearts through mitofilin degradation. Timely inhibition of CPN1/2 represents a promising strategy to reduce cardiac injury and improve DCD heart function.
    Keywords:  MPTP; calpain inhibitor; cyclophilin D; heart transplantation; mitochondria; mitofilin
    DOI:  https://doi.org/10.3390/cells15100920
  3. Nat Commun. 2026 May 25.
    Reconstructing calcium conductance in MCUb illuminates its molecular design for tuning the mitochondrial calcium uniporter.
    I-Chi Lee, Po-Hsuan Lai, Chen-Wei Tsai, Yung-Chi Tu, Yu-Chen Huang, Wei-Chen Chen, Ming-Feng Tsai.
      The mitochondrial Ca2+ uniporter mediates mitochondrial Ca2+ uptake to regulate cellular bioenergetics, Ca2+ signaling and survival, but excessive activity triggers Ca2+ overload and tissue injury. Cells counter this threat by expressing MCUb, a paralog of the uniporter's pore-forming MCU subunit, to attenuate uniporter activity. Despite harboring the conserved Ca2+-coordinating DIME motif, MCUb paradoxically lacks conductance, a defining yet enigmatic feature underlying its uniporter-inhibitory role. Here, we demonstrate that MCUb's non-conductivity stems from its inability to bind EMRE, a subunit essential for uniporter function, and that its N-terminal domain (NTD) exerts autoinhibition. Reinstating EMRE binding and relieving NTD-mediated inhibition rebuild Ca2+ conductance in MCUb, reaching ~80% of MCU activity. Wild-type MCUb exhibits ~30% of the inhibitory capacity of a pore-disrupting E249A variant, indicating that MCUb is a modest, rather than potent, negative regulator. These findings reveal how MCU-MCUb paralog divergence endows the uniporter with regulatory plasticity to fine-tune mitochondrial Ca2+ homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-73711-y
  4. Nat Commun. 2026 May 26.
    Pathogenic variants in the autophagy-tethering factor EPG5 drive neurodegeneration through mitochondrial dysfunction and innate immune activation.
    Kritarth Singh, Hormos Salimi Dafsari, Olivia Gillham, Haoyu Chi, Ivet Mandzhukova, Ioanna Kourouzidou, Preethi Sheshadri, Chih-Yao Chung, Valeria Pingitore, Fleur Vansenne, David L Selwood, Diana Pendin, Gyorgy Szabadkai, Manolis Fanto, Heinz Jungbluth, Michael R Duchen.
      The autophagy-tethering factor ectopic P-granule 5 autophagy protein (EPG5) plays a key role in autophagosome-lysosome fusion. Impaired autophagy associated with pathogenic variants in EPG5 causes a rare devastating multisystem disorder known as Vici syndrome, which features neurodevelopmental defects, severe progressive neurodegeneration and immunodeficiency. The pathophysiological mechanisms driving disease presentation and progression are only partially understood. In patient-derived fibroblasts and iPS cells differentiated to cortical neurons, we find that impaired mitophagy leads to mitochondrial bioenergetic dysfunction. Physiological cytosolic Ca2+ transients result in unexpected mitochondrial Ca2+ overload despite a decrease in mitochondrial membrane potential. This is attributed to downregulation of MICU1. Ca2+ signals cause mitochondrial depolarisation, mtDNA release and activation of the cGAS-STING pathway, reversed by pharmacological inhibition of the mitochondrial permeability transition pore (mPTP) or of the STING pathway. Thus, we identify a pathophysiological cascade driving disease progression associated with EPG5 deficiency, including impaired mitochondrial bioenergetics, mitochondrial Ca2+ overload, vulnerability to mPTP opening and activation of innate immune signalling, signposting multiple potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-73538-7
  5. bioRxiv. 2026 May 17. pii: 2026.05.15.725497. [Epub ahead of print]
    Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
    Yaw Akosah, Ioannis Azoidis, Dane Jensen, Paolo Bernardi, Evgeny Pavlov.
      Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and cristae dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the sub-organellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K + ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K + influx leads to increase of mitochondrial matrix volume while stimulation of K + efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.
    DOI:  https://doi.org/10.64898/2026.05.15.725497
  6. Int J Mol Sci. 2026 May 12. pii: 4317. [Epub ahead of print]27(10):
    Mitochondrial Calcium Overload Drives mtDNA-cGAS-STING Activation via VDAC1 and MCU Upregulation in Periodontitis.
    Xinyi Cheng, Yu Cai, Yiran Geng, Xiaoying Zang, Jia Liu, Qingxian Luan.
      Periodontitis is a chronic inflammatory disease remaining elusive with its pathogenesis. Mitochondrial dysfunction and aberrant immune activation are implicated, but the underlying mechanisms remain incompletely understood. Given the essential role of Ca2+ homeostasis in maintaining normal mitochondrial function, we investigated the role of mitochondrial calcium (mtCa2+) dysregulation in periodontitis. Gingival tissues from periodontitis patients and healthy controls, as well as cultured gingival fibroblasts stimulated with Porphyromonas gingivalis lipopolysaccharide, were examined using transmission electron microscopy, confocal imaging, flow cytometry, qPCR, and western blotting. Notably, mtCa2+ was overloaded under inflammatory conditions, accompanied by disruption of whole-cell Ca2+ homeostasis. We also observed marked mitochondrial ultrastructural damage, mitochondrial DNA (mtDNA) leakage, and activation of the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway. The mitochondrial Ca2+ channel proteins, voltage dependent anion channel 1 (VDAC1) and mitochondrial calcium uniporter (MCU), were significantly upregulated in periodontitis gingiva, and their expression positively correlated with probing depth. Pharmacological inhibition of VDAC1 or MCU attenuated mtCa2+ overload, reduced mtDNA release and downregulated pro-inflammatory cytokines. These findings link mtCa2+ overload to mtDNA leakage and innate immune activation in periodontitis, and identify VDAC1 and MCU as promising therapeutic targets to restore mtCa2+ homeostasis and control host immune responses.
    Keywords:  MCU; VDAC1; calcium; gingival fibroblasts; mitochondria DNA; periodontitis
    DOI:  https://doi.org/10.3390/ijms27104317
  7. bioRxiv. 2026 May 15. pii: 2026.05.13.724793. [Epub ahead of print]
    A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.
    Sean McCracken, Minglei Zhao, Kyler Squirrell, Christopher Zhao, Saman Behboodi Tanourlouee, Michelle Aum, Philip R Williams.
      Retinal ganglion cells (RGCs) degenerate in optic neuropathies like glaucoma and traumatic optic nerve injury leading to irreversible vision loss. Higher levels of homeostatic Ca 2+ and canonical Ca 2+ regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca 2+ homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca 2+ levels (mito-Ca 2+ ). We find that mito-Ca 2+ is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca 2+ levels. Mitochondrial dysfunction was observed where mito-Ca 2+ was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca 2+ in surviving RGCs by altering mito-Ca 2+ levels and Ca 2+ transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca 2+ increased survival to ONC. We then manipulated mito-Ca 2+ permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca 2+ to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca 2+ and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca 2+ levels.
    DOI:  https://doi.org/10.64898/2026.05.13.724793
  8. Neurochem Res. 2026 May 27. pii: 176. [Epub ahead of print]51(3):
    Ethylmalonic and Methylsuccinic Acids Disrupt Bioenergetics and Induce Mitochondrial Permeability Transition Through Thiol Redox Modulation in Rat Striatum: Potential Mechanisms Involved in Ethylmalonic Encephalopathy.
    Manuela Bianchin Marcuzzo, Ângela Beatris Zemniaçak, Jaqueline Santana da Rosa, Bianca Silveira Signorini Verdi, Maria Paula Dalla Vechia Benati, Josyane de Andrade Silveira, Juliana Gomes do Nascimento, Helena de Almeida Moreira, Mateus Dias-Oliveira, Diogo Onofre Souza, Alexandre Umpierrez Amaral, Geancarlo Zanatta, Moacir Wajner, Guilhian Leipnitz.
      Ethylmalonic (EMA) and methylsuccinic (MSA) acids concentrations are elevated in tissues and body fluids of patients with ethylmalonic encephalopathy (EE), a mitochondrial disorder associated with basal ganglia abnormalities. To clarify the pathophysiology of this disorder, we evaluated the effects of EMA and MSA on bioenergetics, redox homeostasis and mitochondrial permeability transition (MPT) in rat striatum. We verified that EMA and MSA reduced state 3 and uncoupled respiration and inhibited the activities of α-ketoglutarate dehydrogenase and complex IV of the electron transport chain. Both organic acids also decreased mitochondrial membrane potential and Ca2+ retention capacity, which were normalized by cyclosporine A and ADP, indicating induction of MPT pore opening. These effects were further mitigated by N-ethylmaleimide and dithiothreitol, suggesting that thiol groups of the MPT pore were oxidized by EMA and MSA. Moreover, EMA and MSA mildly decreased reduced glutathione concentrations, reinforcing that thiol group are oxidized by these organic acids. Therefore, it is presumed that EMA- and MSA-induced bioenergetic impairment associated with MPT pore opening is involved in the pathophysiology of basal ganglia injury observed in EE.
    Keywords:  Bioenergetics; Ethylmalonic acid; Ethylmalonic encephalopathy; Methylsuccinic acid; Mitochondrial permeability transition; Striatum
    DOI:  https://doi.org/10.1007/s11064-026-04801-y
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