bims-miptne Biomed News
on Mitochondrial permeability transition pore-dependent necrosis
Issue of 2024‒03‒10
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool
  1. The anti-apoptotic role of Ginkgolide B via mitochondrial permeability transition pore inhibition in retinal ischemia-reperfusion.
  2. Targeting cell death pathways in intestinal ischemia-reperfusion injury: a comprehensive review.
  3. Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.
  4. MLKL overexpression leads to Ca2+ and metabolic dyshomeostasis in a neuronal cell model.
  5. Follistatin-like 1 protects against doxorubicin-induced cardiotoxicity by preventing mitochondrial dysfunction through the SIRT6/Nrf2 signaling pathway.
  6. STING dependent BAX-IRF3 signaling results in apoptosis during late-stage Coxiella burnetii infection.
  7. An unexpected journey for BNIP3.
  1. Biochem Biophys Res Commun. 2024 Mar 01. pii: S0006-291X(24)00258-4. [Epub ahead of print]705 149722
    The anti-apoptotic role of Ginkgolide B via mitochondrial permeability transition pore inhibition in retinal ischemia-reperfusion.
    Xiou Wang, Baoqi Hu, Hanyue Zhang, Sijia Zhou, Wenfei Wu, Zizhu Tan, Meiqi Sun, Qianyan Kang.
      This research delves into the effectiveness of Ginkgolide B (GB), a compound from Ginkgo biloba, in combating cell death caused by glaucoma, with a focus on mitochondrial impairment and the mitochondrial permeability transition pore (mPTP). Utilizing models of high intraocular pressure and in vitro glaucoma simulations, the study investigates GB's impact on retinal progenitor cells (RPCs) under oxygen-glucose deprivation/reperfusion (OGD/R) and in a rat glaucoma model. The study methodologies included apoptosis assessment, apoptotic marker analysis via Western blot, and mitochondrial structure and function evaluation. The findings reveal that GB notably decreases apoptosis in RPCs exposed to OGD/R in vitro, and reduces ischemia-reperfusion damage in vivo. GB's protective role is attributed to its ability to preserve mitochondrial integrity, maintain membrane potential, regulate calcium levels, and inhibit mPTP opening. These results underscore GB's potential as a therapeutic agent for acute primary angle-closure glaucoma, highlighting its capability to alleviate mitochondrial damage and apoptosis in RPCs and retinal nerve fiber layer cells.
    Keywords:  Ginkgolide B; Mitochondrial function; OGD/R; Retina nerve fiber layer; Retinal pregenital cells; mPTP
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149722
  2. Cell Death Discov. 2024 Mar 04. 10(1): 112
    Targeting cell death pathways in intestinal ischemia-reperfusion injury: a comprehensive review.
    Fei Wang, Huiming Huang, Xuejiao Wei, Peng Tan, Zhuguo Wang, Zhongdong Hu.
      Intestinal ischemia-reperfusion (I/R) is a multifaceted pathological process, and there is a lack of clear treatment for intestinal I/R injury. During intestinal I/R, oxidative stress and inflammation triggered by cells can trigger a variety of cell death mechanisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necrosis. These cell death processes can send a danger signal for the body to be damaged and prevent intestinal I/R injury. Therefore, identifying key regulatory molecules or markers of these cell death mechanisms when intestinal I/R injury occurs may provide valuable information for the treatment of intestinal I/R injury. This paper reviews the regulatory molecules and potential markers that may be involved in regulating cell death during intestinal I/R and elaborates on the cell death mechanism of intestinal I/R injury at the molecular level to provide a theoretical basis for discovering new molecules or markers regulating cell death during intestinal I/R injury and provides ideas for drug development for the treatment of intestinal I/R injury.
    DOI:  https://doi.org/10.1038/s41420-024-01891-x
  3. Nat Rev Cancer. 2024 Mar 07.
    Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.
    Pascal Meier, Arnaud J Legrand, Dieter Adam, John Silke.
      Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis - a largely immunologically silent form of cell death - there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8+ T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks.
    DOI:  https://doi.org/10.1038/s41568-024-00674-x
  4. Cell Calcium. 2024 Feb 06. pii: S0143-4160(24)00012-5. [Epub ahead of print]119 102854
    MLKL overexpression leads to Ca2+ and metabolic dyshomeostasis in a neuronal cell model.
    Sathyaseelan S Deepa, Nidheesh Thadathil, Jorge Corral, Sabira Mohammed, Sophia Pham, Hadyn Rose, Michael T Kinter, Arlan Richardson, Carlos Manlio Díaz-García.
      The necroptotic effector molecule MLKL accumulates in neurons over the lifespan of mice, and its downregulation has the potential to improve cognition through neuroinflammation, and changes in the abundance of synaptic proteins and enzymes in the central nervous system. Notwithstanding, direct evidence of cell-autonomous effects of MLKL expression on neuronal physiology and metabolism are lacking. Here, we tested whether the overexpression of MLKL in the absence of cell death in the neuronal cell line Neuro-2a recapitulates some of the hallmarks of aging at the cellular level. Using genetically-encoded fluorescent biosensors, we monitored the cytosolic and mitochondrial Ca2+ levels, along with the cytosolic concentrations of several metabolites involved in energy metabolism (lactate, glucose, ATP) and oxidative stress (oxidized/reduced glutathione). We found that MLKL overexpression marginally decreased cell viability, however, it led to reduced cytosolic and mitochondrial Ca2+ elevations in response to Ca2+ influx from the extracellular space. On the contrary, Ca2+ signals were elevated after mobilizing Ca2+ from the endoplasmic reticulum. Transient elevations in cytosolic Ca2+, mimicking neuronal stimulation, lead to higher lactate levels and lower glucose concentrations in Neuro-2a cells when overexpressing MLKL, which suggest enhanced neuronal glycolysis. Despite these alterations, energy levels and glutathione redox state in the cell bodies remained largely preserved after inducing MLKL overexpression for 24-48 h. Taken together, our proof-of-concept experiments are consistent with the hypothesis that MLKL overexpression in the absence of cell death contributes to both Ca2+ and metabolic dyshomeostasis, which are cellular hallmarks of brain aging.
    Keywords:  Aging; Calcium; Lactate; MLKL; Metabolism; Mitochondria; Necroptosis; Neuron
    DOI:  https://doi.org/10.1016/j.ceca.2024.102854
  5. Cell Biol Int. 2024 Mar 04.
    Follistatin-like 1 protects against doxorubicin-induced cardiotoxicity by preventing mitochondrial dysfunction through the SIRT6/Nrf2 signaling pathway.
    Haijun Xu, Hong Guo, Zhigang Tang, Ruijun Hao, Shaowei Wang, Ping Jin.
      Mitochondrial dysfunction and myocardial remodeling have been reported to be the main underlying molecular mechanisms of doxorubicin-induced cardiotoxicity. SIRT6 is a nicotinamide adenine dinucleotide-dependent enzyme that plays a vital role in cardiac protection against various stresses. Moreover, previous studies have demonstrated that FSTL1 could alleviate doxorubicin-induced cardiotoxicity by inhibiting autophagy. The present study investigated the probable mechanisms of FSTL1 on doxorubicin-induced cardiotoxicity in vivo and in vitro. We confirmed that FSTL1 exerted a pivotal protective role on cardiac tissue in vivo and on doxorubicin-induced cell injury in vitro. Furthermore, FSTL1 can alleviate doxorubicin-induced mitochondrial dysfunction by inhibiting autophagy and apoptosis. Further studies demonstrated that FSTL1 can activate SIRT6 signaling by restoring the SIRT6 protein expression in doxorubicin-induced myocardial injury. SIRT6 activation elevated the protein expression of Nrf2 in doxorubicin-induced H9C2 injury. Treatment with the Nrf2 inhibitor ML385 partially antagonized the cardioprotective role of SIRT6 on doxorubicin-induced autophagy or apoptosis. These results suggested that the protective mechanism of FSTL1 on doxorubicin-induced cardiotoxicity may be related with the inhibition of autophagy and apoptosis, partly through the activation of SIRT6/Nrf2.
    Keywords:  FSTL1; SIRT6; apoptosis; autophagy; cardiac remodeling; doxorubicin
    DOI:  https://doi.org/10.1002/cbin.12147
  6. Cell Death Dis. 2024 Mar 08. 15(3): 195
    STING dependent BAX-IRF3 signaling results in apoptosis during late-stage Coxiella burnetii infection.
    Manish Chauhan, Chelsea A Osbron, Heather S Koehler, Alan G Goodman.
      STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii is a Gram-negative obligate intracellular bacterium and the causative agent of the zoonotic disease Q fever. The ability of C. burnetii to inhibit host cell death is a critical factor in disease development. Previous studies have shown that C. burnetii inhibits host cell apoptosis at early stages of infection. However, during the late-stages of infection, there is host cell lysis resulting in the release of bacteria to infect bystander cells. Thus, we investigated the role of STING during late-stages of C. burnetii infection and examined STING's impact on host cell death. We show that the loss of STING results in higher bacterial loads and abrogates IFNβ and IL6 induction at 12 days post-infection. The absence of STING during C. burnetii infection significantly reduces apoptosis through decreased caspase-8 and -3 activation. During infection, STING activates IRF3 which interacts with BAX. BAX then translocates to the mitochondria, which is followed by mitochondrial membrane depolarization. This results in increased cytosolic mtDNA in a STING-dependent manner. The presence of increased cytosolic mtDNA results in greater cytosolic 2'-3' cGAMP, creating a positive feedback loop and leading to further increases in STING activation and its downstream signaling. Taken together, we show that STING signaling is critical for BAX-IRF3-mediated mitochondria-induced apoptosis during late-stage C. burnetii infection.
    DOI:  https://doi.org/10.1038/s41419-024-06573-1
  7. Autophagy. 2024 Mar 06. 1-2
    An unexpected journey for BNIP3.
    José M Delgado, Christopher J Shoemaker.
      Mitophagy is a cellular process that enables the selective degradation of damaged, dysfunctional, or superfluous mitochondria. During mitophagy, specific proteins recognize and tag mitochondria for degradation. These tagged mitochondria are engulfed by specialized structures called phagophores that then mature into autophagosomes/mitophagosomes. Mitophagosomes subsequently transport their mitochondrial cargo to lysosomes, where the mitochondria are broken down and recycled. While the PINK1-PRKN-dependent mitophagy pathway is well understood, mitophagy can also occur independently of this pathway. BNIP3 and BNIP3L/NIX, paralogous membrane proteins on the outer mitochondrial membrane (OMM), serve as ubiquitin-independent mitophagy receptors. Historically, BNIP3 regulation was thought to be primarily transcriptional through HIF1A (hypoxia inducible factor 1 subunit alpha). However, recent work has revealed a significant post-translational dimension, highlighting the strong role of the ubiquitin-proteasome system (UPS) in BNIP3 regulation. With these emerging concepts in mind, we aimed to develop a unified understanding of how steady-state levels of BNIP3 are established and maintained and how this regulation governs underlying cell physiology.
    Keywords:  BNIP3; EMC; ER membrane protein complex; NIX; membrane trafficking; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2312038
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒10 at 14:54.