bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2024–05–26
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Tissue-specific differences in Ca2+ sensitivity of the mitochondrial permeability transition pore (PTP). Experiments in male rat liver and heart.
  2. Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
  3. The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off-target effects.
  4. Deciphering the Molecular Nexus: An In-Depth Review of Mitochondrial Pathways and Their Role in Cell Death Crosstalk.
  5. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
  6. Urolithin A, induces apoptosis and autophagy crosstalk in Oral Squamous Cell Carcinoma via mTOR /AKT/ERK1/2 pathway.
  7. Mitochondrial depolarization and ATP loss during high frequency nanosecond and microsecond electroporation.
  1. Physiol Rep. 2024 May;12(10): e16056
    Tissue-specific differences in Ca2+ sensitivity of the mitochondrial permeability transition pore (PTP). Experiments in male rat liver and heart.
    Carolina Ricardez-Garcia, Mauricio Reyes-Becerril, Edson Mosqueda-Martinez, Ofelia Mendez-Romero, Angelica Ruiz-Ramírez, Salvador Uribe-Carvajal.
      Permeability transition pore (PTP) opening dissipates ion and electron gradients across the internal mitochondrial membrane (IMM), including excess Ca2+ in the mitochondrial matrix. After opening, immediate PTP closure must follow to prevent outer membrane disruption, loss of cytochrome c, and eventual apoptosis. Flickering, defined as the rapid alternative opening/closing of PTP, has been reported in heart, which undergoes frequent, large variations in Ca2+. In contrast, in tissues that undergo depolarization events less often, such as the liver, PTP would not need to be as dynamic and thus these tissues would not be as resistant to stress. To evaluate this idea, it was decided to follow the reversibility of the permeability transition (PT) in isolated murine mitochondria from two different tissues: the very dynamic heart, and the liver, which suffers depolarizations less frequently. It was observed that in heart mitochondria PT remained reversible for longer periods and at higher Ca2+ loads than in liver mitochondria. In all cases, Ca2+ uptake was inhibited by ruthenium red and PT was delayed by Cyclosporine A. Characterization of this phenomenon included measuring the rate of oxygen consumption, organelle swelling and Ca2+ uptake and retention. Results strongly suggest that there are tissue-specific differences in PTP physiology, as it resists many more Ca2+ additions before opening in a highly active organ such as the heart than in an organ that seldom suffers Ca2+ loading, such as the liver.
    Keywords:  calcium; heart mitochondrial; liver mitochondrial; mitochondrial permeability transition; reactive oxygen species; tissue specificity
    DOI:  https://doi.org/10.14814/phy2.16056
  2. Cell Calcium. 2024 May 23. pii: S0143-4160(24)00065-4. [Epub ahead of print]121 102907
    Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
    Denis Vecellio Reane, Julian D C Serna, Anna Raffaello.
      Calcium (Ca2+) signalling acts a pleiotropic message within the cell that is decoded by the mitochondria through a sophisticated ion channel known as the Mitochondrial Ca2+ Uniporter (MCU) complex. Under physiological conditions, mitochondrial Ca2+ signalling is crucial for coordinating cell activation with energy production. Conversely, in pathological scenarios, it can determine the fine balance between cell survival and death. Over the last decade, significant progress has been made in understanding the molecular bases of mitochondrial Ca2+ signalling. This began with the elucidation of the MCU channel components and extended to the elucidation of the mechanisms that regulate its activity. Additionally, increasing evidence suggests molecular mechanisms allowing tissue-specific modulation of the MCU complex, tailoring channel activity to the specific needs of different tissues or cell types. This review aims to explore the latest evidence elucidating the regulation of the MCU complex, the molecular factors controlling the tissue-specific properties of the channel, and the physiological and pathological implications of mitochondrial Ca2+ signalling in different tissues.
    Keywords:  Brain; Calcium signalling; Heart; Liver; MCU regulation; Mitochondrial calcium uniporter; Skeletal Muscle; tissue-specific modulation
    DOI:  https://doi.org/10.1016/j.ceca.2024.102907
  3. Br J Pharmacol. 2024 May 23.
    The mitochondrial calcium uniporter inhibitor Ru265 increases neuronal excitability and reduces neurotransmission via off-target effects.
    Peng Xu, Sarpras Swain, Robyn J Novorolsky, Esperanza Garcia, Zhouyang Huang, Terrance P Snutch, Justin J Wilson, George S Robertson, Robert B Renden.
       BACKGROUND AND PURPOSE: Excitotoxicity due to mitochondrial calcium (Ca2+) overloading can trigger neuronal cell death in a variety of pathologies. Inhibiting the mitochondrial calcium uniporter (MCU) has been proposed as a therapeutic avenue to prevent calcium overloading. Ru265 (ClRu(NH3)4(μ-N)Ru(NH3)4Cl]Cl3) is a cell-permeable inhibitor of the mitochondrial calcium uniporter (MCU) with nanomolar affinity. Ru265 reduces sensorimotor deficits and neuronal death in models of ischemic stroke. However, the therapeutic use of Ru265 is limited by the induction of seizure-like behaviours.
    EXPERIMENTAL APPROACH: We examined the effect of Ru265 on synaptic and neuronal function in acute brain slices and hippocampal neuron cultures derived from mice, in control and where MCU expression was genetically abrogated.
    KEY RESULTS: Ru265 decreased evoked responses from calyx terminals and induced spontaneous action potential firing of both the terminal and postsynaptic principal cell. Recordings of presynaptic Ca2+ currents suggested that Ru265 blocks the P/Q type channel, confirmed by the inhibition of currents in cells exogenously expressing the P/Q type channel. Measurements of presynaptic K+ currents further revealed that Ru265 blocked a KCNQ current, leading to increased membrane excitability, underlying spontaneous spiking. Ca2+ imaging of hippocampal neurons showed that Ru265 increased synchronized, high-amplitude events, recapitulating seizure-like activity seen in vivo. Importantly, MCU ablation did not suppress Ru265-induced increases in neuronal activity and seizures.
    CONCLUSIONS AND IMPLICATIONS: Our findings provide a mechanistic explanation for the pro-convulsant effects of Ru265 and suggest counter screening assays based on the measurement of P/Q and KCNQ channel currents to identify safe MCU inhibitors.
    Keywords:  MCU; calcium overload; mitochondria; mouse; proconvulsants
    DOI:  https://doi.org/10.1111/bph.16425
  4. Cells. 2024 May 17. pii: 863. [Epub ahead of print]13(10):
    Deciphering the Molecular Nexus: An In-Depth Review of Mitochondrial Pathways and Their Role in Cell Death Crosstalk.
    Yumeng Li, Madiha Rasheed, Jingkai Liu, Zixuan Chen, Yulin Deng.
      Cellular demise is a pivotal event in both developmental processes and disease states, with mitochondrial regulation playing an essential role. Traditionally, cell death was categorized into distinct types, considered to be linear and mutually exclusive pathways. However, the current understanding has evolved to recognize the complex and interconnected mechanisms of cell death, especially within apoptosis, pyroptosis, and necroptosis. Apoptosis, pyroptosis, and necroptosis are governed by intricate molecular pathways, with mitochondria acting as central decision-makers in steering cells towards either apoptosis or pyroptosis through various mediators. The choice between apoptosis and necroptosis is often determined by mitochondrial signaling and is orchestrated by specific proteins. The molecular dialogue and the regulatory influence of mitochondria within these cell death pathways are critical research areas. Comprehending the shared elements and the interplay between these death modalities is crucial for unraveling the complexities of cellular demise.
    Keywords:  apoptosis; mitochondria; necroptosis; pyroptosis
    DOI:  https://doi.org/10.3390/cells13100863
  5. J Cell Sci. 2024 May 24. pii: jcs.261728. [Epub ahead of print]
    KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
    Peace Atakpa-Adaji, Adelina Ivanova, Karolina Kujawa, Colin W Taylor.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the ER to the cytosol and, at specialised membrane contact sites (MCS), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These 'licensed' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCS. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondria membrane contact sites (ERMCS) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCS. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCS.
    Keywords:  Ca2+; Endoplasmic reticulum; HeLa cell; Histamine; IP3 receptor; KRAP; MCU; Membrane contact site; Mitochondria; Proximity ligation assay; VDAC1
    DOI:  https://doi.org/10.1242/jcs.261728
  6. Phytomedicine. 2024 May 06. pii: S0944-7113(24)00380-5. [Epub ahead of print]130 155721
    Urolithin A, induces apoptosis and autophagy crosstalk in Oral Squamous Cell Carcinoma via mTOR /AKT/ERK1/2 pathway.
    Viji Remadevi, Vishnu Sunil Jaikumar, Ravindran Vini, Biju Krishnendhu, Juberiya M Azeez, Sankar Sundaram, S Sreeja.
       BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in the world with an alarming rate of mortality. Despite the advancement in treatment strategies and drug developments, the overall survival rate remains poor. Therefore, it is imperative to develop alternative or complimentary anti cancer drugs with minimum off target effects. Urolithin A, a microbial metabolite of ellagic acid and ellagitannins produced endogenously by human gut micro biome is considered to have anti-cancerous activity. However anti tumorigenic effect of urolithin A in OSCC is yet to be elucidated. In this study, we examined whether urolithin A inhibits cell growth and induces both apoptosis and autophagy dependent cell death in OSCC cell lines.
    PURPOSE: The present study aims to evaluate the potential of urolithin A to inhibit OSCC and its regulatory effect on OSCC proliferation and invasion in vitro and in vivo mouse models.
    METHODS: We evaluated whether urolithin A could induce cell death in OSCC in vitro and in vivo mouse models.
    RESULTS: Flow cytometric and immunoblot analysis on Urolithin A treated OSCC cell lines revealed that urolithin A markedly induced cell death of OSCC via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. This further revealed a possible cross talk between apoptotic and autophagic signaling pathways. In vivo study demonstrated that urolithin A treatment reduced tumor size and showed a decrease in mTOR, ERK1/2 and Akt levels along with a decrease in proliferation marker, Ki67. Taken together, in vitro as well as our in vivo data indicates that urolithin A is a potential anticancer agent and the inhibition of AKT/mTOR/ERK signalling is crucial in Urolithin A induced growth suppression in oral cancer.
    CONCLUSION: Urolithin A exerts its anti tumorigenic activity through the induction of apoptotic and autophagy pathways in OSCC. Our findings suggest that urolithin A markedly induced cell death of oral squamous cell carcinoma via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. Urolithin A remarkably suppressed tumor growth in both in vitro and in vivo mouse models signifying its potential as an anticancer agent in the prevention and treatment of OSCC. Henceforth, our findings provide a new insight into the therapeutic potential of urolithin A in the prevention and treatment of OSCC.
    Keywords:  AKT/MTOR/ERK signaling; Apoptosis; Autophagy; OSCC; Urolithin A
    DOI:  https://doi.org/10.1016/j.phymed.2024.155721
  7. Bioelectrochemistry. 2024 May 18. pii: S1567-5394(24)00104-X. [Epub ahead of print]159 108742
    Mitochondrial depolarization and ATP loss during high frequency nanosecond and microsecond electroporation.
    Paulina Malakauskaitė, Augustinas Želvys, Auksė Zinkevičienė, Eglė Mickevičiūtė, Eivina Radzevičiūtė-Valčiukė, Veronika Malyško-Ptašinskė, Barbora Lekešytė, Jurij Novickij, Vytautas Kašėta, Vitalij Novickij.
      It is predicted that ultra-short electric field pulses (nanosecond) can selectively permeabilize intracellular structures (e.g., mitochondria) without significant effects on the outer cell plasma membrane. Such a phenomenon would have high applicability in cancer treatment and could be employed to modulate cell death type or immunogenic response. Therefore, in this study, we compare the effects of 100 µs x 8 pulses (ESOPE - European Standard Operating Procedures on Electrochemotherapy) and bursts of 100 ns pulses for modulation of the mitochondria membrane potential. We characterize the efficacies of various protocols to trigger permeabilization, depolarize mitochondria (evaluated 1 h  after treatment), the extent of ATP depletion and generation of reactive oxygen species (ROS). Finally, we employ the most prominent protocols in the context of Ca2+ electrochemotherapy in vitro. We provide experimental proof that 7.5-12.5 kV/cm x 100 ns pulses can be used to modulate mitochondrial potential, however, the permeabilization of the outer membrane is still a prerequisite for depolarization. Similar to 100 µs x 8 pulses, the higher the permeabilization rate, the higher the mitochondrial depolarization. Nevertheless, 100 ns pulses result in lesser ROS generation when compared to ESOPE, even when the energy input is several-fold higher than for the microsecond procedure. At the same time, it shows that even the short 100 ns pulses can be successfully used for Ca2+ electrochemotherapy, ensuring excellent cytotoxic efficacy.
    Keywords:  Burst compression; Calcium electrochemotherapy; High-frequency; Membrane potential; Mitochondria
    DOI:  https://doi.org/10.1016/j.bioelechem.2024.108742
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