bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2025–01–12
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Point of No Return-What Is the Threshold of Mitochondria With Permeability Transition in Cells to Trigger Cell Death.
  2. Differential effects of endo- and exopolyphosphatase expression on the induction of the mitochondrial permeability transition pore.
  3. Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.
  4. Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.
  5. A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
  6. A Comprehensive Insight into Apoptosis: Molecular Mechanisms, Signaling Pathways, and Modulating Therapeutics.
  1. J Cell Physiol. 2025 Jan;240(1): e31521
    Point of No Return-What Is the Threshold of Mitochondria With Permeability Transition in Cells to Trigger Cell Death.
    Kristina A Kritskaya, Olga A Stelmashchuk, Andrey Y Abramov.
      Programmed cell death (apoptosis) is essential part of the process of tissue regeneration that also plays role in the mechanism of pathology. The phenomenon of fast and transient permeability of mitochondrial membranes by various triggers, known as permeability transition pore (mPTP) leads to the release of proapoptotic proteins and acts as an initial step in initiation of apoptosis. However, a role for mPTP was also suggested for physiology and it is unclear if there is a threshold in number of mitochondria with mPTP which induces cell death and how this mechanism is regulated in different tissues. Using simultaneous measurements of mitochondrial membrane potential and a fluorescent marker for caspase-3 activation we studied the number of mitochondria with calcium-induced mPTP opening necessary for induction of apoptosis in rat primary cortical neurons, astrocytes, fibroblasts, and cancer (BT-474) cells. The induction of apoptosis was correlated with 80%-90% mitochondrial signal loss in neural cells but only 35% in fibroblasts, and in BT-474 cancer cells over 90% of mitochondria opens mPTP before apoptosis becomes obvious. The number of mitochondria with mPTP which induce cell death did not correlate with total expression levels of proapoptotic proteins but was consistent with the Bax/Bcl-2 ratio in these cells. Calcium-induced mPTP opening increased levels of necrosis which was higher in fibroblasts compared to neurons, astrocytes and BT-474 cells. Thus, different tissues require specific numbers of mitochondria with PTP opening to induce apoptosis and it correlates to the proapoptotic/antiapoptotic proteins expression ratio in them.
    Keywords:  apoptosis; astrocytes; caspase‐3; fibroblasts; mPTP; mitochondria; necrosis; neurons
    DOI:  https://doi.org/10.1002/jcp.31521
  2. Biochim Biophys Acta Biomembr. 2025 Jan 07. pii: S0005-2736(25)00002-1. [Epub ahead of print] 184408
    Differential effects of endo- and exopolyphosphatase expression on the induction of the mitochondrial permeability transition pore.
    Akosah Yaw, Vedangi Hambardikar, Maria Neginskaya, Sally Morris, Maria E Solesio, Evgeny V Pavlov.
      Inorganic polyphosphate (polyP) is a polymer that consists of a series of orthophosphates connected by high-energy phosphoanhydride bonds, like those found in ATP. In mammalian mitochondria, polyP has been linked to the activation of the mitochondrial permeability transition pore (mPTP). However, the details of this process are not completely understood. The activation of mPTP by polyP may involve the regulation of bioenergetics, Ca2+ buffering, or direct involvement in mPTP channel formation. In this study, using refractive index imaging techniques, we examined mPTP induction in both wild-type (WT) SH-SY5Y cells, and mutant SH-SY5Y cells expressing either mitochondrially targeted exopolyphosphatase (MitoPPX), which depletes polyP by breaking free terminal phosphoanhydride bonds; or endopolyphosphatase (MitoPPN), which cleaves internal phosphoanhydride bonds and thus can target polyP pool with protected terminal groups. Upon treating the cells with the calcium ionophore ferutinin, the influx of Ca2+ triggered mitochondrial membrane depolarization and permeabilization in both WT and MitoPPX cells indicating activation of mPTP. However, in MitoPPN cells, mitochondrial depolarization occurred without mPTP activation. Based on these findings we propose the possibility that activation of mPTP is not linked to the pool of free polyP. This supports the hypothesis that polyP is either an important structural component of the mPTP channel or associated with other macromolecular complexes involved in mPTP induction.
    Keywords:  Holographic imaging; Mitochondria; Permeability transition; Polyphosphate
    DOI:  https://doi.org/10.1016/j.bbamem.2025.184408
  3. Front Immunol. 2024 ;15 1503087
    Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.
    Fan Chen, Kedong Xu, Yimin Han, Jiachun Ding, Jiaqiang Ren, Yaochun Wang, Zhenhua Ma, Fang Cao.
      Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.
    Keywords:  acute pancreatitis; calcium overload; mitochondrial; mitochondrial permeability transition pore; regulated cell death
    DOI:  https://doi.org/10.3389/fimmu.2024.1503087
  4. Cell Commun Signal. 2025 Jan 09. 23(1): 17
    Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.
    Xuexin Li, Xin Zhao, Zhengshan Qin, Jie Li, Bowen Sun, Li Liu.
      This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation-contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a "quasi-synaptic" mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.
    Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12964-024-02014-w
  5. Biochim Biophys Acta Mol Cell Res. 2025 Jan 05. pii: S0167-4889(25)00005-9. [Epub ahead of print] 119900
    A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
    Martin Hirtl, Benjamin Gottschalk, Olaf A Bachkoenig, Furkan E Oflaz, Corina Madreiter-Sokolowski, Morten Andre Høydal, Wolfgang F Graier.
      The uptake of Ca2+ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca2+ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca2+. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.
    Keywords:  Inner mitochondrial membrane (IMM); Mitochondrial calcium uniporter (MCU); Mitochondrial calcium uptake 1 (MICU1); Stimulated-emission depletion (STED); Structured illumination microscopy (SIM)
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119900
  6. Cancer Invest. 2025 Jan 06. 1-26
    A Comprehensive Insight into Apoptosis: Molecular Mechanisms, Signaling Pathways, and Modulating Therapeutics.
    Mehrdad Mosadegh, Narjes Noori Goodarzi, Yousef Erfani.
      Apoptosis, or programmed cell death, is a fundamental biological process essential for maintaining tissue homeostasis. Dysregulation of apoptosis is implicated in a variety of diseases, including cancer, neurodegenerative disorders, and autoimmune conditions. This review provides an in-depth insight into the molecular mechanisms and signaling pathways that regulate apoptosis, highlighting both intrinsic and extrinsic pathways. Additionally, the review explains the tumor microenvironment's influence on apoptosis and its implications for cancer therapy resistance. Understanding the complex interplay between apoptotic signaling and cellular responses is crucial for developing targeted therapies that can effectively manage diseases associated with apoptosis dysregulation. The effects of conventional therapeutics and alternative substances with natural sources such as herbal compounds, alongside vitamins, minerals, and trace elements on cellular homeostasis and disease pathogenesis have been thoroughly investigated. Moreover, recent advances in therapeutic strategies aimed at modulating apoptosis are discussed, with a focus on novel interventions such as nutrition bio shield dietary supplement. These emerging approaches offer potential benefits beyond conventional treatments by selectively targeting apoptotic pathways to inhibit cancer progression and metastasis. By integrating insights from recent studies, this review aims to enhance our understanding of apoptosis and guide future research in developing innovative therapeutic approaches.
    Keywords:  Apoptosis; cancer; extrinsic pathway; intrinsic pathway; nutrients
    DOI:  https://doi.org/10.1080/07357907.2024.2445528
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