bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–07–20
twelve papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Atad3 is Essential for Mitochondrial Permeability Transition Pore Opening and Cardiac Ischemia Reperfusion Injury.
  2. MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
  3. Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes.
  4. N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea-based inhibitors of cyclophilin D - Preparation of distinct stereoisomers and comparative analysis of their in vitro bioactivity.
  5. Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
  6. Specialized high-capacity mitochondria fuel cell invasion.
  7. Harnessing tissue-derived mitochondria-rich extracellular vesicles (Ti-mitoEVs) to boost mitochondrial biogenesis for regenerative medicine.
  8. Mitochondrial p32-mediated regulation of p-TBK1 affects the radiosensitivity of colorectal cancer.
  9. The calcium homeostasis in tumor and the mechanism involving progression and metastasis.
  10. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
  11. Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?
  12. Calcium ion-binding genes can predict tumor mutation burden and immune checkpoint blockade response in a pan-cancer model.
  1. bioRxiv. 2025 Jun 17. pii: 2025.06.13.658955. [Epub ahead of print]
    Atad3 is Essential for Mitochondrial Permeability Transition Pore Opening and Cardiac Ischemia Reperfusion Injury.
    Dexter Robichaux, Sual J Lopez, Arielys Mendoza, Daniel Ramirez, Suh-Chin J Lin, Jeffery D Molkentin, Pablo M Peixoto, Jason Karch.
      The molecular identity of the mitochondrial permeability transition pore (mPTP) has remained elusive since the discovery of its existence over 75 years ago. Despite the numerous candidate proteins proposed, none have withstood genetic ablation, leaving them relegated to auxiliary regulatory roles. To date, no essential mPTP component has been identified. Here, we establish ATAD3 as the first essential component of the mPTP. Genetic deletion of Atad3 in cardiomyocytes and hepatocytes renders heart and liver mitochondria incapable of undergoing Ca 2+ -induced mPTP-dependent swelling. Moreover, these mitochondria exhibit the highest Ca 2+ retention capacity ever reported following genetic perturbation of the mPTP. Furthermore, patch-clamp recordings of recombinant ATAD3a in liposomes reveal intrinsic channel activity. Given the established role of mPTP-dependent necrosis in driving ischemia/reperfusion (I/R) injury, we show that cardiac-specific Atad3 deletion markedly reduces infarct size following I/R, with no additive protection from cyclosporine A. Together, these findings establish ATAD3 as an core, putative pore-forming component essential for mPTP opening and mPTP-dependent necrosis, resolving a long-standing mystery in mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.06.13.658955
  2. Res Sq. 2025 Jun 26. pii: rs.3.rs-6346822. [Epub ahead of print]
    MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
    John Elrod, Henry Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Joanne Garbincius, Adyson Johnson, Tyler Stevens, Jordan Howe, Emily Megill, Jennyfer Ngo, Dhanendra Tomar, Nathaniel Snyder, Wolfgang Graier.
      Mitochondrial matrix Ca2+ concentration ([matrixCa2+]) 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. This begs the question, what are the primary molecular mechanisms regulating calcium-dependent changes in metabolism? The primary function of MICU proteins (MICU1, MICU2, and MICU3) is reported to be gatekeeping of the mtCU and regulating mitochondrial Ca2+ uptake. Here, we demonstrate that MICU proteins function in coordination to impart Ca2+-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independent of the mtCU and [matrixCa2+]. 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. Utilizing an equimolar expression platform coupled with unbiased proteomics we reveal unique interactomes for MICU1/2 versus MICU1/3 heterodimers and demonstrate that MICU proteins control coupling of Mitochondrial Glycerol-3-Phosphate Dehydrogenase with Succinate Dehydrogenase/Complex II and impart Ca2+-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 Ca2+ signaling mechanism regulating homeostatic energetics - not mtCU-dependent changes in [matrixCa2+].
    DOI:  https://doi.org/10.21203/rs.3.rs-6346822/v1
  3. J Am Heart Assoc. 2025 Jul 17. e039220
    Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes.
    Olha M Koval, Emily K Nguyen, Dylan J Mittauer, Jane L Buchanan, Kyle Westhoff, Dao-Fu Dai, Eric B Taylor, Isabella M Grumbach.
       BACKGROUND: Excessive proliferation of vascular smooth muscle cells (VSMCs) is a consequence of type 2 diabetes (T2D) that increases the risk for atherosclerosis and restenosis after angioplasty. Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on increased reactive oxygen species and intracellular [Ca2+] that both drive cell proliferation, occur in T2D, and are regulated by the mitochondrial Ca2+ uniporter (MCU).
    METHODS: Using a mouse model of T2D, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. The T2D model was induced by high-fat diet and low-dose streptozotocin in both wild type mice and mice with the VSMC-specific inhibition of the mtCaMKII (mitochondrial Ca2+/calmodulin-dependent kinase IImtCaMKII), a regulator of Ca2+ entry via the MCU.
    RESULTS: In VSMCs from T2D model mice, MCU inhibition reduced both in vivo neointima formation after mechanical injury, as well as in vitro proliferation of cultured VSMCs. Further, in VSMCs from T2D mice, the composition of the MCU complex and MCU activity were altered with loss of MICU1 (mitochondrial calcium uptake 1). In addition, VSMC mitochondrial reactive oxygen species was elevated and mitochondrial respiration blunted. The increase in cytosolic reactive oxygen species induced activation of G6PD (glucose-6-phosphate dehydrogenase), a key enzyme of the pentose phosphate pathway. However, inhibiting MCU or MICU1 overexpression on VSMCs from T2D mice decreased intracellular reactive oxygen species, preserved mitochondrial respiration and ATP production, decreased activity of G6PD, and normalized cell proliferation. These data suggest the MCU complex controls a T2D-induced metabolic switch that promotes cell proliferation.
    CONCLUSIONS: Collectively, these data indicate that MCU complex remodeling in T2D drives neointimal restenosis, suggesting MCU as a therapeutic target.
    Keywords:  diabetes; metabolism; mitochondria; neointima; vascular smooth muscle cells
    DOI:  https://doi.org/10.1161/JAHA.124.039220
  4. Bioorg Chem. 2025 Jul 10. pii: S0045-2068(25)00623-6. [Epub ahead of print]163 108743
    N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea-based inhibitors of cyclophilin D - Preparation of distinct stereoisomers and comparative analysis of their in vitro bioactivity.
    Annamaria Haleckova, Katarina Jurkova, Jan Hurdalek, Katarina Chalupova, Veronika Syrova, Dominika Kozlov, Jana Svobodova, Rudolf Andrys, Oleksandr Kozlov, Charline Monnier, Rene Endlicher, Adam Skarka, Kamil Musilek, Lucie Zemanova, Ondrej Benek.
      Cyclophilin D (CypD) is a mitochondrial enzyme and the key regulator of mitochondrial permeability transition pore (mPTP). Inhibition of CypD/mPTP holds promise as a therapeutic strategy for treatment of variety of diseases including ischemia-reperfusion injury, or neurodegeneration. Compounds based on the N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea structural scaffold present the most potent class of small-molecule CypD inhibitors identified to date. Numerous independent studies on their synthesis and evaluation were published by different research groups. Unfortunately, the results of particular studies cannot be compared due to use of distinct methods of in vitro evaluation and, in most cases, unresolved stereochemistry of prepared chiral compounds. This did not allow for comprehensive analysis to identify the best inhibitors and their structural features. Therefore, we decided to synthesize the most potent inhibitors and their close analogues in form of pure stereoisomers to perform a side-by-side comparison of their inhibition potency and binding affinity to CypD as well as their ability to suppress mPTP opening. In addition, the selectivity of inhibition has been determined using CypA as an off-target. Compound 13(R) was found superior to other tested small molecule inhibitors in all the tested parameters and it was equipotent to the reference inhibitor cyclosporine A.
    Keywords:  cyclophilin D (CypD); enzyme inhibition; mitochondria; mitochondrial permeability transition pore (mPTP); protein-ligand interaction
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108743
  5. Nat Chem Biol. 2025 Jul 15.
    Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
    Guinevere L Grice, Eleanor Minogue, Hudson W Coates, Mekdes Debela, Richard J Stopforth, Niek Wit, Zongyu Li, Joseph P Crowley, Arthur Kaser, Nicole Kaneider-Kaser, P Robin Antrobus, Marcia C Haigis, Randall S Johnson, James A Nathan.
      Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.
    DOI:  https://doi.org/10.1038/s41589-025-01965-6
  6. bioRxiv. 2025 May 03. pii: 2025.05.02.651978. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Caitlin Su, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive, and how an invading cell produces high ATP levels to power invasion is understudied. By generating 20 endogenously tagged mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP to fuel invasion. These ETC-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through a Src kinase directs microtubule polarization, which facilitates metaxin adaptor complex dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP by generating and localizing high-capacity mitochondria. This might be common strategy used by other cells to meet energy demanding processes.
    DOI:  https://doi.org/10.1101/2025.05.02.651978
  7. Sci Adv. 2025 Jul 18. 11(29): eadt1318
    Harnessing tissue-derived mitochondria-rich extracellular vesicles (Ti-mitoEVs) to boost mitochondrial biogenesis for regenerative medicine.
    Peng Lou, Xiyue Zhou, Yimeng Zhang, Yijing Xie, Yizhuo Wang, Chengshi Wang, Shuyun Liu, Meihua Wan, Yanrong Lu, Jingping Liu.
      Mitochondrial damage is a critical pathological factor in various forms of tissue injury, and specific therapies with high biosafety are desirable. Inspired by the natural role of extracellular vesicles (EVs) in regulating mitochondrial metabolism, we report that healthy tissue-derived mitochondria-rich EVs (Ti-mitoEVs) can boost mitochondrial biogenesis for regenerative medicine. Ti-mitoEVs that contain abundant functional mitochondria can be highly efficiently isolated from muscles via an optimized method. In vitro, Ti-mitoEV treatment increased mitochondrial biogenesis and reduced mitochondrial damage in recipient cells, and these effects occurred at least partly via mitochondrial genome transfer. In vivo, Ti-mitoEV treatment attenuated diverse types of tissue injury (e.g., muscle and kidney) by rescuing mitochondrial injury and its associated inflammation. As natural nanovesicles, the therapeutic potency of mitoEVs can be further improved by integrating them with other engineering methods. This study highlights the promising role of Ti-mitoEVs in boosting mitochondrial biogenesis, positioning them as potential therapies for treating various types of tissue injury characterized by mitochondrial damage.
    DOI:  https://doi.org/10.1126/sciadv.adt1318
  8. Life Sci. 2025 Jul 12. pii: S0024-3205(25)00489-8. [Epub ahead of print] 123854
    Mitochondrial p32-mediated regulation of p-TBK1 affects the radiosensitivity of colorectal cancer.
    Yanjin Wu, Haitao Zhou, Jiahui Meng, Wenyue Zhao, Xiaotong Zhao, Yujia Hou, Qin Wang, Feng Wang, Qiang Liu, Yang Liu.
       PURPOSE: Many colorectal cancer (CRC) patients respond poorly to radiotherapy due to radioresistance. Understanding the molecular mechanisms underlying this resistance is crucial. It was demonstrated that p32, a mitochondrial protein translation regulator, is related to cancer development. However, its specific function and mechanism in CRC, has not yet been investigated. This study aims to explore the role of p32 in CRC and its impact on radiotherapy sensitivity.
    METHODS: Cell viability was evaluated by MTT and EdU assay. Mitochondrial DNA (mtDNA) leakage was quantified by RT-qPCR. Radiosensitivity was indicated by cellular phosphorylation of H2AX (γH2AX) foci, phosphorylation of ataxia telangiectasia mutated (p-ATM) and phosphorylation of checkpoint kinase 2 (p-CHK2) levels, as well as by mice tumor model subjected to radiotherapy. Moreover, histological and transcriptomic analysis of p32 expression were performed in CRC patients.
    RESULTS: In p32-KO cells, we observed reduced cell viability, damaged mitochondria, mtDNA leakage, and increased radiosensitivity. Furthermore, depletion of p32 induced the DNA damage response (DDR) by activating cytoplasmic DNA sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1), which was reversed by p32/TBK1 double knockout. Depletion of p32 also induced the mitochondrial fragmentation, induced mtDNA leakage through the mitochondrial permeability transition pore (mPTP), effects that could be mitigated by Mdivi-1 or Cyclosporin A (CsA).
    CONCLUSIONS: Our study demonstrates that inhibiting p32 in CRC enhances radiosensitivity by causing mitochondrial dysfunction, increasing mitochondrial fission, inducing mtDNA leakage and activating the cGAS-STING-TBK1 pathway. These findings provide a potential therapeutic target for overcoming radioresistance in CRC.
    Keywords:  Mitochondria dysfunction; Radiosensitivity; cGAS-STING-TBK1; mPTP; mtDNA
    DOI:  https://doi.org/10.1016/j.lfs.2025.123854
  9. Cancer Lett. 2025 Jul 11. pii: S0304-3835(25)00476-8. [Epub ahead of print] 217908
    The calcium homeostasis in tumor and the mechanism involving progression and metastasis.
    Zhenpu Qin, Yuqin Di, Tianrong Ma, Wei Zeng, Xianzhi Liu, Weiling He.
      Calcium ions (Ca2+) act as important intracellular second messengers and play a key role in cellular physiological functions and signal transduction. Ca2+ significantly affects the biological behavior of tumor cells by regulating mechanisms, such as cytoskeleton reorganization, cell migration, invasion, and immune escape. Although research on calcium homeostasis in tumor progression and metastasis was historically limited, it has recently received widespread attention. Growing evidence indicates that the disruption of calcium homeostasis is closely linked to the development, invasion, and metastasis of tumors. This paper systematically reviews the mechanisms governing calcium homeostasis in tumor progression and metastasis. We focused on calcium channels, pumps, and their regulatory roles in ionic signaling networks, the tumor microenvironment, downstream signaling pathways, and immune escape. We also discussed therapeutic strategies targeting tumor progression and metastasis via the modulation of calcium homeostasis. By elucidating the role of calcium homeostasis in tumor metastasis, this review aims to provide a theoretical foundation and to identify potential targets for novel anti-metastatic strategies.
    Keywords:  Calcium ion homeostasis; Cell migration; Signaling pathway; Tumor metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217908
  10. Nat Immunol. 2025 Jul 16.
    Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
    Elizabeth M Steinert, Beatriz Furtado Bruza, Veronika D Danchine, Rogan A Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E Weinberg, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites1. Mitochondrial electron transport is required for T cell proliferation2-4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8+ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8+ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8+ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8+ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.
    DOI:  https://doi.org/10.1038/s41590-025-02202-x
  11. Int J Mol Sci. 2025 Jun 26. pii: 6138. [Epub ahead of print]26(13):
    Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?
    Sebastian Neumann, Rolf Heumann.
      The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; voltage-dependent anion channels
    DOI:  https://doi.org/10.3390/ijms26136138
  12. Discov Oncol. 2025 Jul 16. 16(1): 1341
    Calcium ion-binding genes can predict tumor mutation burden and immune checkpoint blockade response in a pan-cancer model.
    Wan-Yu Lin, Chien-Jung Huang, Yu-Chao Wang.
       BACKGROUND: Tumor mutation burden (TMB), the total number of nonsynonymous mutations in the tumor genome, is a well-established biomarker for predicting responses to immune checkpoint blockade (ICB) therapy across various cancers. Patients with high TMB tend to exhibit better responses to ICB. Recently, targeted gene panels have been developed to estimate TMB before treatment. These panels are enriched for calcium ion-binding genes. However, a direct link between TMB and calcium ion-binding genes has not been reported in the literature to date.
    METHODS: The association between TMB and calcium ion-binding genes was analyzed using mutation data from The Cancer Genome Atlas (TCGA) database. In addition, a pan-cancer model was constructed to estimate TMB based solely on calcium ion-binding genes. The model's predictive power for ICB response was validated using independent datasets. Finally, enrichment analysis was performed to investigate the biological connections between calcium ion-binding genes and TMB.
    RESULTS: Calcium ion-binding genes were enriched among the TMB-predictive model genes in 27 out of 33 cancer types. Among these, 19 cancer types exhibited strong predictive performance, with R² values greater than 0.5 in our pan-cancer model based on calcium ion-binding genes. The model effectively estimated TMB and identified ICB responders in independent datasets, including lung adenocarcinoma and melanoma. Enrichment analysis further suggested that calcium ion-binding genes may influence TMB through signal transduction pathways.
    CONCLUSIONS: These findings establish a novel association between calcium ion-binding genes and TMB, demonstrating the feasibility of a pan-cancer TMB estimation model based on calcium ion-binding genes. This approach may enhance TMB estimation and improve ICB response prediction across multiple cancers.
    Keywords:  Calcium ion-binding genes; Immune checkpoint blockade (ICB); Pan-cancer model; Signal transduction; Tumor mutation burden (TMB)
    DOI:  https://doi.org/10.1007/s12672-025-03184-w
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