bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–02–02
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst.
  2. Twist-Induced Epithelial-to-Mesenchymal Transition Confers Specific Metabolic and Mitochondrial Alterations.
  3. Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial-Mesenchymal Transition.
  4. The roles of mitochondria in global and local intracellular calcium signalling.
  5. Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies.
  6. Multiomic analysis of lactylation and mitochondria-related genes in hepatocellular carcinoma identified MRPL3 as a new prognostic biomarker.
  1. Oncol Res. 2025 ;33(2): 397-406
    MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst.
    Edmund Cheung So, Louis W C Chow, Chin-Min Chuang, Cing Yu Chen, Cheng-Hsun Wu, Lian-Ru Shiao, Ting-Tsz Ou, Kar-Lok Wong, Yuk-Man Leung, Yi-Ping Huang.
       Objectives: Mitochondrial Ca2+ uniporter (MCU) provides a Ca2+ influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca2+ rise stimulates ATP production and cell growth. MCU is highly expressed in various cancer cells including breast cancer cells, thereby increasing the capacity of mitochondrial Ca2+ uptake, ATP production, and cancer cell proliferation. The objective of this study was to examine MCU inhibition as an anti-cancer mechanism.
    Methods: The effects of MCU-i4, a newly developed MCU inhibitor, on cell viability, apoptosis, cytosolic Ca2+, mitochondrial Ca2+ and potential, glycolytic rate, generation of ATP, and reactive oxygen species, were examined in breast cancer BT474 cells.
    Results: MCU-i4 caused apoptotic cell death, and it decreased and increased, respectively, mitochondrial and cytosolic Ca2+ concentration. Inhibition of MCU by MCU-i4 revealed that cytosolic Ca2+ elevation resulted from endoplasmic reticulum (ER) Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RYR). Unexpectedly, MCU-i4 enhanced glycolysis and ATP production; it also triggered a large production of reactive oxygen species (ROS) and mitochondrial membrane potential collapse.
    Conclusion: Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS. It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis. Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.
    Keywords:  BT474 cells; Breast cancer; Cell death; MCU-i4; Mitochondria Ca2+ uniporter (MCU)
    DOI:  https://doi.org/10.32604/or.2024.052743
  2. Cells. 2025 Jan 09. pii: 80. [Epub ahead of print]14(2):
    Twist-Induced Epithelial-to-Mesenchymal Transition Confers Specific Metabolic and Mitochondrial Alterations.
    Haleigh N Parker, Kayla L Haberman, Tolulope Ojo, Juli Watkins, Adhwaitha Nambiar, Kayla Morales, Bernd Zechmann, Joseph H Taube.
      Cells undergo significant epigenetic and phenotypic change during the epithelial-to-mesenchymal transition (EMT), a process observed in development, wound healing, and cancer metastasis. EMT confers several advantageous characteristics, including enhanced migration and invasion, resistance to cell death, and altered metabolism. In disease, these adaptations could be leveraged as therapeutic targets. Here, we analyze Twist-induced EMT in non-transformed HMLE cells as well as a breast cancer cell line with (MDA-MB-231) and without (MCF7) EMT features to compare differences in metabolic pathways and mitochondrial morphology. Analysis of oxidative and glycolytic metabolism reveals a general EMT-associated glycolytic metabolic phenotype accompanied by increased ATP production. Furthermore, a decrease in mitochondrial size was also associated with EMT-positive cells. However, mitochondrial elongation and spatial dynamics were not consistently altered, as HMLE Twist cells exhibit more rounded and dispersed mitochondria compared to control, while MDA-MB-231 cells exhibit more elongated and clustered mitochondria compared to MCF7 cells. These results provide further insight as to the contextual nature of EMT conferred properties.
    Keywords:  EMT; TNBC; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells14020080
  3. Cancers (Basel). 2025 Jan 12. pii: 228. [Epub ahead of print]17(2):
    Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial-Mesenchymal Transition.
    Ewa Błaszczak, Paulina Miziak, Adrian Odrzywolski, Marzena Baran, Ewelina Gumbarewicz, Andrzej Stepulak.
      Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial-mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes.
    Keywords:  EMT; EMT markers; TNBC; chemoresistance; epithelial–mesenchymal transition; resistance; treatment; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers17020228
  4. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  5. Front Immunol. 2024 ;15 1513047
    Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies.
    Wenjuan Wang, Hong Wang, Qi Wang, Xiaojing Yu, Liangliang Ouyang.
      Lactate, long viewed as a byproduct of glycolysis and metabolic waste. Initially identified within the context of yogurt fermentation, lactate's role extends beyond culinary applications to its significance in biochemical processes. Contemporary research reveals that lactate functions not merely as the terminal product of glycolysis but also as a nexus for initiating physiological and pathological responses within the body. Lysine lactylation (Kla), a novel post-translational modification (PTM) of proteins, has emerged as a pivotal mechanism by which lactate exerts its regulatory influence. This epigenetic modification has the potential to alter gene expression patterns, thereby impacting physiological and pathological processes. Increasing evidence indicates a correlation between lactylation and adverse prognosis in various malignancies. Consequently, this review article aims to encapsulate the proteins that interact with lactate, elucidate the role of lactylation in tumorigenesis and progression, and explore the potential therapeutic targets afforded by the modulation of lactylation. The objective of this review is to clarify the oncogenic significance of lactylation and to provide a strategic framework for future research directions in this burgeoning field.
    Keywords:  cancer; lactate; lactylation; post-translational modification; proteins interacting with lactate
    DOI:  https://doi.org/10.3389/fimmu.2024.1513047
  6. Front Oncol. 2024 ;14 1511958
    Multiomic analysis of lactylation and mitochondria-related genes in hepatocellular carcinoma identified MRPL3 as a new prognostic biomarker.
    Wenya Xing, Yuanzi Zhou, Qiuzi Long, Nan Yi, Gaoyuan Wang, Rongwei Shi, Jinlong Huang, Xindong Yin, Taiyang Zhu, Shibing Cao.
       Background: Recent research has highlighted lactate's crucial role in epigenetic regulation, particularly by influencing histone modifications that drive the initiation and progression of hepatocellular carcinoma (HCC). While mitochondria are known to regulate tumor behavior, the interaction between lactate metabolism and mitochondrial function in cancer tissues remains underexplored. Understanding this relationship may provide deeper insights into tumor metabolic reprogramming and reveal novel therapeutic targets for HCC and other malignancies.
    Methods: We conducted a comprehensive screening of lactylation- and mitochondria-associated genes (LMRGs) in HCC patients, followed by clustering based on these genes. Prognostic outcomes and pathway enrichment were analyzed across the identified clusters. Additionally, we developed a prognostic model based on LMRGs, examining its implications for survival, immune response, and drug sensitivity. In vitro experiments were performed to validate the expression patterns and functional role of MRPL3 in HCC.
    Results: We developed a prognostic model, named the LMRG model, incorporating three key genes: ACACA, MRPL3, and MRPS23. This model revealed significant differences in survival outcomes, immune responses, and drug sensitivity between patients with high and low LMRG scores. MRPL3 was found to be overexpressed in HCC, playing a critical role in tumor growth and metastasis. These results were further validated through in vitro experiments, confirming MRPL3's role in HCC cell proliferation and invasion.
    Conclusion: We created a predictive model, LMRG, and identified MRPL3 as a key biomarker. Our findings suggest that MRPL3 has significant potential as a reliable predictive biomarker for clinical applications in HCC diagnosis and treatment.
    Keywords:  MRPL3; epigenetic regulation; hepatocellular carcinoma; lactylation; prognostic biomarkers
    DOI:  https://doi.org/10.3389/fonc.2024.1511958
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