bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–06–01
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy.
  2. Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration.
  3. Adenine nucleotide-dependent Ca2+ buffering by mitochondria in an inorganic phosphate-free medium.
  4. Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
  5. Identification of circulating tumor cells marker genes as prognostic signature in triple-negative breast cancer.
  6. Emerging role of mitochondrial calcium levels in cellular senescence and in switching cell fates.
  7. SERCA activation prevents Ca2+ and ATP upregulation during three-day soleus muscle unloading in rats.
  1. ACS Chem Neurosci. 2025 May 29.
    Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy.
    Yaqiong Li, Junkui Shang, Huiwen Zhang, Yaru Lu, Ying Zhao, Yadan Wang, Xi Yan, Jiewen Zhang.
      Chronic cerebral hypoperfusion (CCH) results in cognitive impairment, with mitochondrial dysfunction identified as a key contributor. The opening of the mitochondrial permeability transition pore (mPTP) is closely associated with mitochondrial dysfunction and excessive mitophagy, particularly under stress conditions. Dl-3-n-Butylphthalide (Dl-NBP) has been shown to ameliorate cognitive impairment caused by CCH. However, whether Dl-NBP exerts its effects by inhibiting mPTP opening and mitigating excessive mitophagy remains unclear. In this study, we established a rat model of CCH through permanent bilateral common carotid artery occlusion (BCCAO) and explored the neuroprotective effects of Dl-NBP and its underlying mechanisms. The neuroprotective effects of Dl-NBP were evaluated using the Morris water maze test, and protein expression levels related to mPTP, apoptosis, and mitophagy were assessed through Western blotting and immunofluorescence. The ultrastructural changes in mitochondrial morphology and mitophagosomes were observed using transmission electron microscopy. We found that CCH led to cognitive impairment in rats, along with increased expression of p53, cytochrome-c, cleaved-Caspase3, LC3II/LC3I, Beclin1, P62, PINK1, and Parkin in the hippocampal tissue. Additionally, CCH caused an accumulation of mitophagosomes in the hippocampal tissue, although it did not affect Cyclophilin D (CypD) expression levels. However, Dl-NBP reversed these changes, except for CypD. Taken together, these findings suggest that Dl-NBP may improve cognitive impairment in CCH rats, potentially through the reduction of hippocampal neuron apoptosis by inhibiting mPTP opening and excessive mitophagy. Dl-NBP may represent a potential therapeutic strategy for treating cognitive impairment associated with CCH.
    Keywords:  Dl-3-n-butylphthalide; chronic cerebral hypoperfusion; mitochondrial permeability transition pore; mitophagy; vascular dementia
    DOI:  https://doi.org/10.1021/acschemneuro.4c00826
  2. Front Cell Neurosci. 2025 ;19 1570596
    Mitochondria: the hidden engines of traumatic brain injury-driven neurodegeneration.
    Olusola A Olatona, Sydney P Sterben, Sahan B S Kansakar, Aviva J Symes, Volha Liaudanskaya.
      Mitochondria play a critical role in brain energy metabolism, cellular signaling, and homeostasis, making their dysfunction a key driver of secondary injury progression in traumatic brain injury (TBI). This review explores the relationship between mitochondrial bioenergetics, metabolism, oxidative stress, and neuroinflammation in the post-TBI brain. Mitochondrial dysfunction disrupts adenosine triphosphate (ATP) production, exacerbates calcium dysregulation, and generates reactive oxygen species, triggering a cascade of neuronal damage and neurodegenerative processes. Moreover, damaged mitochondria release damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), Cytochrome C, and ATP, triggering inflammatory pathways that amplify tissue injury. We discuss the metabolic shifts that occur post-TBI, including the transition from oxidative phosphorylation to glycolysis and the consequences of metabolic inflexibility. Potential therapeutic interventions targeting mitochondrial dynamics, bioenergetic support, and inflammation modulation are explored, highlighting emerging strategies such as mitochondrial-targeted antioxidants, metabolic substrate supplementation, and pharmacological regulators of mitochondrial permeability transition pores. Understanding these mechanisms is crucial for developing novel therapeutic approaches to mitigate neurodegeneration and enhance recovery following brain trauma.
    Keywords:  bioenergetics; brain injury; metabolism; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3389/fncel.2025.1570596
  3. Biochim Biophys Acta Bioenerg. 2025 May 26. pii: S0005-2728(25)00025-8. [Epub ahead of print]1866(3): 149559
    Adenine nucleotide-dependent Ca2+ buffering by mitochondria in an inorganic phosphate-free medium.
    Anna B Nikiforova, Maxim V Molchanov, Alexey G Kruglov.
      Inorganic phosphate (Pi) is essential for Ca2+ buffering by mitochondria. Adenine nucleotides (AN) are known to strongly increase the Ca2+-retention capacity (CRC) of mitochondria even in the absence of Pi in the medium. Several mechanisms can explain this phenomenon. Here we examined these mechanisms in detail in isolated rat liver mitochondria. We found that, in Pi-free medium, AN dose-dependently increased the CRC. The FOF1-ATP synthase (F-ATPase) inhibitor oligomycin decreased the CRC and the Ca2+ uptake rate to a minor extent. Nuclear magnetic resonance (NMR) analysis showed that Pi in suspensions of oligomycin-treated mitochondria was formed due to AN hydrolysis. In the absence and presence of Ca2+, mitochondria accumulated small and large (50 and > 1000 nmol/mg protein) amounts of Pi, respectively, without detectable accumulation of AN. The average ratio of Ca2+ to Pi accumulated by intact mitochondria in the presence of ADP, ATP, and ATP plus Pi was about 0.68, 1, and 1.25, respectively, or lower. These values correspond to the formation of calcium dihydrogen and hydrogen orthophosphates, and tricalcium phosphate/whitlockite in different proportions. AN increased the CRC in the presence of inhibitors of both F-ATPase and adenylate translocase, the known regulators of the permeability transition pore (PTP). The PTP inhibitor NADH did not increase the CRC in the absence of Pi. Thus, the mechanism of the AN-dependent increase in the CRC in the absence of Pi includes the F-ATPase-independent production of Pi and suppression of the PTP at the site other than F-ATPase and adenylate translocase.
    Keywords:  ADP; ATP; Ca(2+)-retention capacity; Mitochondria; NMR spectroscopy; Permeability transition pore; Phosphate
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149559
  4. Sci Adv. 2025 May 30. 11(22): eadu9512
    Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
    Nicole M Marsh, Melissa J S MacEwen, Jane Chea, Heidi L Kenerson, Albert A Kwong, Timothy M Locke, Francisco Javier Miralles, Tanmay Sapre, Natasha Gozali, Madeleine L Hart, Theo K Bammler, James W MacDonald, Lucas B Sullivan, G Ekin Atilla-Gokcumen, Shao-En Ong, John D Scott, Raymond S Yeung, Yasemin Sancak.
      Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adu9512
  5. Discov Oncol. 2025 May 24. 16(1): 915
    Identification of circulating tumor cells marker genes as prognostic signature in triple-negative breast cancer.
    Jia Hu, Kai-Ming Zhang, Xi Wang.
       BACKGROUND: Breast cancer represents a significant contributor to cancer-related mortality among women worldwide, with triple-negative breast cancer (TNBC) often exhibiting more aggressive clinical features and a heightened lethality rate. The emergence of malignant progression, along with issues of drug resistance, poses substantial challenges in the clinical management of this disease.
    METHODS: The analysis of gene expression profiles at the single-cell level was conducted on circulating tumor cells (CTCs) obtained from TNBC patients, with the objective of identifying specific marker genes associated with CTCs. The TCGA database served as the training cohort for the development of a prognostic CTCs signature model, while the METABRIC dataset was utilized as the validation cohort to assess the robustness of the CTCs signature model. Furthermore, we investigated the differences in prognosis, immune scores, tumor mutational burden, and responses to immunotherapy and chemotherapy across various risk groups established based on the CTCs signature model. Colony formation and transwell assays were conducted to assess the influence of CTCs signature genes on cellular proliferation and invasive capabilities.
    RESULTS: Seven marker genes associated with CTCs (BLOC1S3, FOXD2, GZMB, KCNJ13, NTRK3, SOAT2, and ZNF589) were identified and incorporated into a CTCs signature model. The risk score derived from this model stratified TNBC patients into high-risk and low-risk groups. Notably, the overall survival (OS) rate for the low-risk group was significantly higher than that of the high-risk group. Furthermore, the low-risk cohort exhibited more favorable prognostic outcomes and demonstrated heightened sensitivity to both immunotherapy and chemotherapy. Finally, knockdown experiments conducted in TNBC cell lines demonstrated that CTCs signature genes play a crucial role in the regulation of cellular proliferation and invasion.
    CONCLUSION: The CTCs signature model offers novel insights into the prognostic significance of CTC marker genes in TNBC. This understanding may serve as a valuable reference for predicting responses to immunotherapy and chemotherapy, as well as for revealing the molecular mechanisms and therapeutic targets of TNBC.
    Keywords:  Chemotherapy response; Circulating tumor cells; Immunotherapy; Marker genes; Prognostic model; Triple-negative breast cancers
    DOI:  https://doi.org/10.1007/s12672-025-02604-1
  6. Nat Aging. 2025 May 26.
    Emerging role of mitochondrial calcium levels in cellular senescence and in switching cell fates.
    Céline Margand, Pablo Morgado-Cáceres, Ulises Ahumada-Castro, J César Cárdenas, Nadine Martin, David Bernard.
      
    DOI:  https://doi.org/10.1038/s43587-025-00887-1
  7. Am J Physiol Regul Integr Comp Physiol. 2025 May 28.
    SERCA activation prevents Ca2+ and ATP upregulation during three-day soleus muscle unloading in rats.
    Ksenia Askhatovna Zaripova, Svetlana P Belova, Kristina A Sharlo, Darya A Sidorenko, Tatiana Y Kostrominova, Boris S Shenkman, Tatiana L Nemirovskaya.
      Background. The imbalance in the ratio of protein synthesis versus protein degradation results in skeletal muscle atrophy following unloading. The onset of these processes is regulated by the sarcoplasmic concentrations of ATP and calcium (Ca2+). We tested the hypothesis that unloading-induced inactivation of SERCA results in raised Ca2+ concentrations, triggering catabolic processes. CDN1163, an activator of SERCA, was used to test this hypothesis. Methods. Three groups of male rats were used: control rats with intraperitoneal injection of placebo (C), 3 days of unloading with placebo injection (3HS), and 3 days of unloading injected with CDN1163 (3HSC). Results. Treatment with CDN1163 during three days of soleus muscle unloading prevented the upregulation of Ca2+ and ATP, and the slow-to-fast shift in muscle fiber composition. This treatment blocked the decrease in the phosphorylation of the anabolic markers (GSK3b, eEF2, and S6(Ser240/244/ Ser235/236)), and therefore it is likely that it improved the efficiency of translation in the unloaded muscle, but it did not affect mTORC1-dependent signaling. Treatment with CDN1163 also modulated the regulation of the Ca2+-dependent signaling in muscle during unloading via SERCA1 and CSQ2, and changes in the CaMKII phosphorylation and the content of IP3R. In addition, CDN1163 prevented the upregulation of the mRNA expression of MuRF1 (but not MAFbx) and attenuated the increase of Cbl-b and ubiquitin mRNA expression during unloading. Conclusions. Activation of SERCA with CDN1163 prevents the upregulation of Ca2+ and ATP, as well as calcium-dependent and ubiquitin-proteasome pathways markers, and improves protein translation efficiency in three-day unloaded soleus muscle.
    Keywords:  AMPK; ATP; CaMKII; MuRF1; atrophy; unloading
    DOI:  https://doi.org/10.1152/ajpregu.00177.2024
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