bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–08–24
four papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool



  1. Adv Sci (Weinh). 2025 Aug 19. e05666
      Although regenerative endodontics demonstrate promise for dental pulp regeneration, chronic inflammation often hinders the success. This study aims to explore the mechanism whereby lipopolysaccharide (LPS) induces dental pulp regeneration failure. Transcriptomic profiling of LPS-stimulated dental pulp stem cells (DPSCs) reveals dysregulated cation homeostasis and increased magnesium (Mg2⁺) transmembrane transport. Mechanistically, LPS is observed to activate the transcription factor signal transducer and activator of transcription 5A (STAT5A), which binds to the solute carrier family 41 member 1 (SLC41A1) promoter, thereby upregulating the Mg2⁺ efflux transporter and depleting intracellular Mg2⁺ levels. Mg2⁺ efflux destabilizes the mitochondrial permeability transition pore (mPTP), thus facilitating its opening via the interaction of oligomycin sensitivity-conferring protein (OSCP) and cyclophilin D (CypD), which releases reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) and exacerbates oxidative stress. The released mtDNA activates the absent in melanoma 2 (AIM2) inflammasome, thereby amplifying gasdermin D (GSDMD)-mediated pyroptosis. Exogenous supplementation with Mg2⁺ restores intracellular Mg2⁺ homeostasis, suppresses mPTP opening, and reduces mtDNA and ROS leakage, thereby rescuing DPSCs viability and differentiation capacity. This study identifies SLC41A1-mediated Mg2⁺ dysregulation as a pivotal driver of LPS-induced mitochondrial damage and demonstrates that Mg2⁺ replenishment is a therapeutic strategy to counteract inflammation-driven regenerative failure.
    Keywords:  dental stem cell; magnesium ion; mitochondrial permeability transition pore; pyroptosis; solute carrier family 41 member 1
    DOI:  https://doi.org/10.1002/advs.202505666
  2. Cell Death Dis. 2025 Aug 16. 16(1): 622
      Cell death regulation is essential for stress adaptation and/or signal response. Past studies have shown that eukaryotic cell death is mediated by an evolutionarily conserved enzyme, arginyltransferase1 (Ate1). The downregulation of Ate1, as seen in many types of cancer, prominently increases cellular tolerance to a variety of stress conditions. Conversely, in yeast and mammalian cells, Ate1 is elevated under acute oxidative stress conditions, and this change appears to be essential for triggering cell death. However, studies of Ate1 were conventionally focused on its function in inducing protein degradation via the N-end rule pathway in the cytosol, leading to an incomplete understanding of the role of Ate1 in cell death. Our recent investigation shows that Ate1 dually exists in the cytosol and mitochondria, the latter of which has an established role in cell death initiation. Here, by using budding yeast as a model organism, we found that mitochondrial translocation of Ate1 is promoted by the presence of oxidative stressors, and this process is essential for inducing cell death preferentially through the apoptotic pathway. Also, we found that Ate1-induced cell death is dependent on the formation of the mitochondrial permeability transition pore and at least partly dependent on the action of mitochondria-contained factors, including the apoptosis-inducing factor, but is not directly dependent on mitochondrial electron transport chain activity or reactive oxygen species (ROS) derived from it. Furthermore, our evidence suggests that, contrary to widespread assumptions, the cytosolic protein degradation pathways, including ubiquitin-proteasome, autophagy, or endoplasmic reticulum (ER) stress response, has little or negligible impacts on Ate1-induced cell death in the tested conditions. We conclude that Ate1 controls the mitochondria-dependent cell death pathway.
    DOI:  https://doi.org/10.1038/s41419-025-07917-1
  3. Commun Biol. 2025 Aug 19. 8(1): 1249
      Cardiovascular diseases are often associated with impairment in mitochondrial function. However, existing respirometry measuring mitochondrial function are limited by the necessity of fresh tissue samples. This study develops a method with tailored substrate-inhibitor titration (TSIT) of mitochondrial electron transport complexes (ETC) to measure mitochondrial function in frozen cardiac samples using high-resolution respirometry. Briefly, acetyl-CoA is added to fuel the tricarboxylic acid (TCA) cycle for NADH production, enabling complex I (CI)-linked respiratory assessment. NADH is then added to measure maximum CI-linked respiratory capacity, followed by rotenone and succinate to assess complex II (CII)-linked respiratory capacity. TSIT detects mitochondrial functional differences between frozen atrial and ventricular tissue, with comparable results as measured in fresh samples. It also detects cardiac mitochondrial dysfunction across various (patho)physiological mouse models and in human frozen cardiac samples, highlighting its clinical potential. Furthermore, we provides the first evidence for SC formation between the ETC-SCs and the TCA cycle metabolon using blue native electrophoresis, underpinning why TSIT is feasible in frozen tissue. In conclusion, we establish a novel, robust, sensitive and translational method (TSIT) for assessing mitochondrial (dys)function in frozen cardiac samples from various species, enabling flexible analysis of mitochondrial function in both laboratory and clinical settings.
    DOI:  https://doi.org/10.1038/s42003-025-08608-5
  4. Phytother Res. 2025 Aug 19.
      Flavonoids have a chemo-preventive effect on cancer due to their antioxidant properties and ability to limit proliferation, suppress angiogenesis, and modulate the immune system through cellular death. The immense potential of natural flavonoids in initiating diverse signaling cascades offers a compelling strategy to combat uncontrolled cell proliferation. In disease therapeutics and chemo-prevention, flavonoids have attracted considerable attention due to their ability to activate a range of Programmed cell death (PCD) pathways. PCD is a fundamental mechanism in developmental and defensive systems, with several sub-types based on cell death execution and distinct morphological characteristics. Recent comprehensive studies on cell death have unveiled new insights into various types of cellular destruction and their crucial involvement in the treatment of diseases, including cancer. This review aims to provide a concise yet comprehensive overview of programmed cell death and the impact of flavonoids on initiating these diverse forms of cellular demise. It will delve into the mechanisms through which flavonoids exert their effects, focusing on their potential in cancer prevention and their role in elucidating the molecular pathways underlying programmed cell death. Additionally, the review will explore how comprehending the mechanisms of drugs targeting different cell death pathways in therapy, in both preclinical and clinical studies, may contribute to developing novel therapeutic regimens and mitigating resistance to previously employed medicines.
    Keywords:  PANaptosis; apoptosis; autophagy; cuproptosis; disulfidoptosis; ferroptosis; flavonoids; necrosptosis; pyroptosis
    DOI:  https://doi.org/10.1002/ptr.70018