bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2024–04–07
six papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells.
  2. Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice.
  3. Neuroprotective mechanisms of luteolin in glutamate-induced oxidative stress and autophagy-mediated neuronal cell death.
  4. Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis.
  5. Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
  6. Role of mitochondria in renal ischemia-reperfusion injury.
  1. Free Radic Res. 2024 Apr 05. 1-12
    Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells.
    Upasana Ganguly, Sukhpal Singh, Aritri Bir, Arindam Ghosh, Sankha Shubhra Chakrabarti, Reena V Saini, Luciano Saso, Marco Bisaglia, Sasanka Chakrabarti.
      Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines.
    Keywords:  Mitochondria; cyclosporine A; ferrostatin-1; liproxstatin-1; mitochondrial permeability transition pore
    DOI:  https://doi.org/10.1080/10715762.2024.2336563
  2. Cell Mol Neurobiol. 2024 Apr 03. 44(1): 32
    Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice.
    Hiromitsu Sasaki, Ichiro Nakagawa, Takanori Furuta, Shohei Yokoyama, Yudai Morisaki, Yasuhiko Saito, Hiroyuki Nakase.
      The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-KATP) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca2+ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca2+ concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca2+ concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca2+ concentrations against I/R injury.
    Keywords:  Ischemic postconditioning (PostC); Mitochondrial calcium uniporter (MCU); Mitochondrial permeability transition pore (mPTP); NMDA receptor (NMDAR)
    DOI:  https://doi.org/10.1007/s10571-024-01464-7
  3. Sci Rep. 2024 04 02. 14(1): 7707
    Neuroprotective mechanisms of luteolin in glutamate-induced oxidative stress and autophagy-mediated neuronal cell death.
    Wudtipong Vongthip, Sunita Nilkhet, Kanokkan Boonruang, Monruedee Sukprasansap, Tewin Tencomnao, Seung Joon Baek.
      Neurodegenerative diseases, characterized by progressive neuronal dysfunction and loss, pose significant health challenges. Glutamate accumulation contributes to neuronal cell death in diseases such as Alzheimer's disease. This study investigates the neuroprotective potential of Albizia lebbeck leaf extract and its major constituent, luteolin, against glutamate-induced hippocampal neuronal cell death. Glutamate-treated HT-22 cells exhibited reduced viability, altered morphology, increased ROS, and apoptosis, which were attenuated by pre-treatment with A. lebbeck extract and luteolin. Luteolin also restored mitochondrial function, decreased mitochondrial superoxide, and preserved mitochondrial morphology. Notably, we first found that luteolin inhibited the excessive process of mitophagy via the inactivation of BNIP3L/NIX and inhibited lysosomal activity. Our study suggests that glutamate-induced autophagy-mediated cell death is attenuated by luteolin via activation of mTORC1. These findings highlight the potential of A. lebbeck as a neuroprotective agent, with luteolin inhibiting glutamate-induced neurotoxicity by regulating autophagy and mitochondrial dynamics.
    Keywords:  Autophagy; Luteolin; Mitophagy; Neuroprotection; mTORC1 signaling pathway
    DOI:  https://doi.org/10.1038/s41598-024-57824-2
  4. J Cardiovasc Transl Res. 2024 Apr 03.
    Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis.
    Senlin Ma, Yun Song, Yanxin Xu, Chao Wang, Yifan Yang, Yanchao Zheng, Qiuxin Lu, Qingjiang Chen, Jian Wu, Bin Wang, Mingquan Chen.
      Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.
    Keywords:  Mild therapeutic hypothermia; Mitochondrial apoptosis pathway; Myocardial ischemia/reperfusion injury; SLC25A10
    DOI:  https://doi.org/10.1007/s12265-024-10503-z
  5. JCI Insight. 2024 Apr 02. pii: e169213. [Epub ahead of print]
    Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.
    Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P Taddeo, Cynthia Shu, Orian S Shirihai, Etty Bachar-Wikstrom, Jakob D Wikstrom.
      Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation ihas been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired re-epithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, whilst its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif knockout mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.
    Keywords:  Collagens; Dermatology; Mitochondria; Skin
    DOI:  https://doi.org/10.1172/jci.insight.169213
  6. FEBS J. 2024 Apr 03.
    Role of mitochondria in renal ischemia-reperfusion injury.
    Ruizhen Huang, Chiyu Zhang, Zhengjie Xiang, Tao Lin, Jian Ling, Honglin Hu.
      Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) has a high morbidity and mortality, representing a worldwide problem. The kidney is an essential organ of metabolism that has high blood perfusion and is the second most mitochondria-rich organ after the heart because of the high ATP demands of its essential functions of nutrient reabsorption, acid-base and electrolyte balance, and hemodynamics. Thus, these energy-intensive cells are particularly vulnerable to mitochondrial dysfunction. As the bulk of glomerular ultrafiltrate reabsorption by proximal tubules occurs via active transport, the mitochondria of proximal tubules must be equipped for detecting and responding to fluctuations in energy availability to guarantee efficient basal metabolism. Any insults to mitochondrial quality control mechanisms may lead to biological disruption, blocking the clearance of damaged mitochondria and resulting in morphological change and tissue dysfunction. Extensive research has shown that mitochondria have pivotal roles in acute kidney disease, so in this article, we discuss the role of mitochondria, their dynamics and mitophagy in renal ischemia-reperfusion injury.
    Keywords:  mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; renal ischemia–reperfusion injury
    DOI:  https://doi.org/10.1111/febs.17130
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