bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–09–01
eightteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Cytosine methylation flags mitochondrial RNA for degradation.
  2. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  3. The Minimal Membrane Requirements for BAX-induced Pore Opening upon Exposure to Oxidative Stress.
  4. Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
  5. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
  6. Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway.
  7. P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
  8. POLG-related mitochondrial disease mimicking autoimmune encephalitis.
  9. Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
  10. Accumulation of mitochondrial DNA with a point mutation in tRNALeu(UUR) gene induces brain dysfunction in mice.
  11. The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
  12. Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells.
  13. Mitochondrial membrane lipids in the regulation of bioenergetic flux.
  14. INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
  15. Protein Kinase R (PKR) as a Novel dsRNA Sensor in Antiviral Innate Immunity.
  16. MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.
  17. Mitochondrial DNA Leakage Promotes Persistent Pancreatic Acinar Cell Injury in Acute Pancreatitis via the cGAS-STING-NF-κB Pathway.
  18. Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human β-cells.
  1. Trends Biochem Sci. 2024 Aug 23. pii: S0968-0004(24)00188-9. [Epub ahead of print]
    Cytosine methylation flags mitochondrial RNA for degradation.
    Emeline Recazens, Alexis A Jourdain.
      Mitochondrial double-stranded RNA (dsRNA) can form spontaneously in mitochondria, blocking mitochondrial gene expression and triggering an immune response. A recent study by Kim, Tan, et al. identified a safeguard mechanism in which NOP2/Sun RNA methyltransferase 4 (NSUN4)-mediated RNA methylation (m5C) recruits the RNA degradation machinery to prevent dsRNA formation.
    Keywords:  5-methylcytosine; RNA degradation; dsRNA; immunity; mitochondrial RNA; nucleic acid sensing
    DOI:  https://doi.org/10.1016/j.tibs.2024.08.001
  2. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
  3. Biophys J. 2024 Aug 26. pii: S0006-3495(24)00564-2. [Epub ahead of print]
    The Minimal Membrane Requirements for BAX-induced Pore Opening upon Exposure to Oxidative Stress.
    Paweł Mystek, Vandana Singh, Matěj Horváth, Karolína Honzejková, Petra Riegerová, Hüseyin Evci, Martin Hof, Tomáš Obšil, Radek Šachl.
      Perforation of the outer mitochondrial membrane triggered by BAX and facilitated by its main activator cBID is a fundamental process in cell apoptosis. Here, we employ a newly designed correlative approach based on a combination of a fluorescence cross-correlation binding with a calcein permeabilization assay to understand the involvement of BAX in pore formation under oxidative stress conditions. To mimic the oxidative stress, we enriched liposomal membranes by phosphatidylcholines with truncated sn-2 acyl chains terminated by a carboxyl or aldehyde moiety. Our observations revealed that oxidative stress enhances proapoptotic conditions involving accelerated pore opening kinetics. This enhancement is achieved through increased recruitment of BAX to the membrane and facilitation of BAX membrane insertion. Despite these effects, the fundamental mechanism of pore formation remained unchanged, suggesting an all-or-none mechanism. In line with this mechanism, we demonstrated that the minimal number of BAX molecules at the membrane necessary for pore formation remains constant regardless of BAX activation by cBID or the presence of oxidized lipids. Overall, our findings give a comprehensive picture of the molecular mechanisms underlying apoptotic pore formation and highlight the selective amplifying role of oxidized lipids in triggering formation of membrane pores.
    DOI:  https://doi.org/10.1016/j.bpj.2024.08.017
  4. Nat Commun. 2024 Aug 27. 15(1): 7352
    Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
    William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.
      The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51680-4
  5. Nat Commun. 2024 Aug 26. 15(1): 7337
    Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
    Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta.
      There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-51780-1
  6. J Transl Med. 2024 Aug 28. 22(1): 796
    Blockade of the mitochondrial DNA release ameliorates hepatic ischemia-reperfusion injury through avoiding the activation of cGAS-Sting pathway.
    Yi Xiong, Jiawen Chen, Wei Liang, Kun Li, Yingqi Huang, Jingwen Song, Baoyu Zhang, Xiusheng Qiu, Dongbo Qiu, Qi Zhang, Yunfei Qin.
       BACKGROUND: Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated.
    METHODS: Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models.
    RESULTS: Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization.
    CONCLUSIONS: The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
    Keywords:  Hepatic ischemia-reperfusion injury; Innate immunity; STING; cGAS; mtDNA
    DOI:  https://doi.org/10.1186/s12967-024-05588-8
  7. Nat Commun. 2024 Aug 28. 15(1): 7458
    P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
    Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.
      Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
    DOI:  https://doi.org/10.1038/s41467-024-51901-w
  8. J Neurol. 2024 Aug 24.
    POLG-related mitochondrial disease mimicking autoimmune encephalitis.
    Michael Bayat, Thomas Harbo, Maryam Anzabi, Allan Bayat, Jan Lykke Scheel Thomsen.
      
    DOI:  https://doi.org/10.1007/s00415-024-12641-5
  9. Cell Death Dis. 2024 Aug 27. 15(8): 626
    Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
    Stephan Tang, Anneke Fuß, Zohreh Fattahi, Carsten Culmsee.
      Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.
    DOI:  https://doi.org/10.1038/s41419-024-07015-8
  10. Pharmacol Res. 2024 Aug 27. pii: S1043-6618(24)00319-0. [Epub ahead of print]208 107374
    Accumulation of mitochondrial DNA with a point mutation in tRNALeu(UUR) gene induces brain dysfunction in mice.
    Kaori Ishikawa, Daiki Miyata, Satoko Hattori, Haruna Tani, Takayoshi Kuriyama, Fan-Yan Wei, Tsuyoshi Miyakawa, Kazuto Nakada.
      Brain functions are mediated via the complex interplay between several complex factors, and hence, identifying the underlying cause of an abnormality within a certain brain region can be challenging. In mitochondrial disease, abnormalities in brain function are thought to be attributed to accumulation of mitochondrial DNA (mtDNA) with pathogenic mutations; however, only few previous studies have directly demonstrated that accumulation of mutant mtDNA induced abnormalities in brain function. Herein, we examined the effects of mtDNA mutations on brain function via behavioral analyses using a mouse model with an A2748G point mutation in mtDNA tRNALeu(UUR). Our results revealed that mice with a high percentage of mutant mtDNA showed a characteristic trend toward reduced prepulse inhibition and memory-dependent test performance, similar to that observed in psychiatric disorders, such as schizophrenia; however, muscle strength and motor coordination were not markedly affected. Upon examining the hippocampus and frontal lobes of the brain, mitochondrial morphology was abnormal, and the brain weight was slightly reduced. These results indicate that the predominant accumulation of a point mutation in the tRNALeu(UUR) gene may affect brain functions, particularly the coordination of sensory and motor functions and memory processes. These abnormalities probably caused by both direct effects of accumulation of the mutant mtDNA in neuronal cells and indirect effects via changes of systemic extracellular environments. Overall, these findings will lead to a better understanding of the pathogenic mechanism underlying this complex disease and facilitate the development of optimal treatment methods.
    Keywords:  Brain dysfunction; Environmental factors; Memory; Mitochondrial DNA; MtDNA tRNA(Leu(UUR)); Prepulse inhibition
    DOI:  https://doi.org/10.1016/j.phrs.2024.107374
  11. Cell Rep. 2024 Aug 27. pii: S2211-1247(24)01039-8. [Epub ahead of print]43(9): 114688
    The glycolytic metabolite methylglyoxal covalently inactivates the NLRP3 inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    Keywords:  CP: Immunology; CP: Metabolism; MICA modification; NLRP3; PGK1; covalent; glycolysis; inflammasome; inflammation; methylglyoxal
    DOI:  https://doi.org/10.1016/j.celrep.2024.114688
  12. Oxf Open Immunol. 2024 ;5(1): iqae004
    Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells.
    Vasile Mihai Sularea, Ruchi Sharma, David C Hay, Cliona O'Farrelly.
      Hepatotropic viruses are amongst the most ubiquitous pathogens worldwide, causing significant morbidity and mortality. As hepatocytes are among the primary targets of these viruses, their ability to mount early effective innate defence responses is of major research interest. Interferon lambda (IFNL) is produced early in response to viral stimulation in other cell types, but hepatocyte production of this interferon is little investigated. Due to the difficulty and significant costs in obtaining and culturing human primary hepatocytes, surrogate systems are widely sought. Here we used induced pluripotent stem (iPS)-derived hepatocyte-like cells (HLCs) to investigate hepatic IFNL expression in response to viral-like ligands. We demonstrate that hepatocytes rely on cytoplasmic pattern recognition receptors (PRRs) such as Protein Kinase RNA-dependent (PKR) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) for the detection of double stranded RNA. Stimulation of HLCs by viral-like RNA ligands activating cytosolic RNA sensors resulted in thousand fold increase of type III interferon gene expression. These results are in contrast with type I IFN expression, which was induced to a lower extent. Concomitant induction of interferon stimulated genes, such as interferon-stimulated gene 15 (ISG15) and CXCL10, indicated the ability of HLCs to activate interferon-dependent activity. These results demonstrate that HLCs mount an innate antiviral response upon stimulation with viral-like RNA characterized by the induction of type III IFN.
    Keywords:  Hepatocyte; RNA sensing; antiviral response; interferon; liver
    DOI:  https://doi.org/10.1093/oxfimm/iqae004
  13. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]
    Mitochondrial membrane lipids in the regulation of bioenergetic flux.
    Stephen Thomas Decker, Katsuhiko Funai.
      Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.
    Keywords:  bioenergetics; mitochondria; phospholipids
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
  14. Res Sq. 2024 Aug 16. pii: rs.3.rs-4720604. [Epub ahead of print]
    INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
    Cara R Schiavon, Yuning Wang, Jasmine W Feng, Stephanie Garrett, Tsung-Chang Sung, Yelena Dayn, Chunxin Wang, Richard J Youle, Omar A Quintero-Carmona, Gerald S Shadel, Uri Manor.
      Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.
    DOI:  https://doi.org/10.21203/rs.3.rs-4720604/v1
  15. Methods Mol Biol. 2025 ;2854 265-282
    Protein Kinase R (PKR) as a Novel dsRNA Sensor in Antiviral Innate Immunity.
    Huibin Yu, Dewi Megawati, Chunfu Zheng, Stefan Rothenberg.
      Protein kinase R (PKR), a key double-stranded RNA (dsRNA)-activated sensor, is pivotal for cellular responses to diverse stimuli. This protocol delineates a comprehensive methodological framework employing single luciferase assays, yeast assays, immunoblot assays, and quantitative PCR (qPCR) to discern and validate PKR activities and their downstream impacts on NF-κB-activating signaling pathways. These methodologies furnish a systematic approach to unraveling the role of PKR as a dsRNA sensor and effector in antiviral innate immunity, enabling in-depth analyses of dsRNA sensor activities.
    Keywords:  Immunoblots; NF-κB pro-inflammatory pathway; PKR; PKR inhibitor; RNA sensor; Single luciferase assay; Yeast assay; eIF2α phosphorylation; qPCR
    DOI:  https://doi.org/10.1007/978-1-0716-4108-8_25
  16. Nat Cardiovasc Res. 2023 Aug;2(8): 778-792
    MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.
    Meng Lin, Huifang Xian, Zhanghua Chen, Shang Wang, Ming Liu, Weiwei Liang, Qin Tang, Yao Liu, Wanming Huang, Di Che, Caiqin Guo, Elina Idiiatullina, Rongli Fang, Mahmoud Al-Azab, Jingjie Chang, Rongze Wang, Xiaojun Li, Xiaoyu Zuo, Yan Zhang, Jincun Zhao, Yaping Tang, Shouheng Jin, Zhengjie He, Du Feng, Liwei Lu, Kang Zhang, Yan Wu, Fan Bai, Andrew M Lew, Jun Cui, Yuzhang Wu, Xiaoqiong Gu, Yuxia Zhang.
      Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.
    DOI:  https://doi.org/10.1038/s44161-023-00314-x
  17. Inflammation. 2024 Aug 24.
    Mitochondrial DNA Leakage Promotes Persistent Pancreatic Acinar Cell Injury in Acute Pancreatitis via the cGAS-STING-NF-κB Pathway.
    Deyu Zhang, Jiayu Li, Linlin Zhao, Zhenghui Yang, Chang Wu, Yue Liu, Wanshun Li, Zhendong Jin, Jiayi Ma.
      Previous research has shown that the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages can promote severe acute pancreatitis through the release of inflammatory factors. The role of this pathway in pancreatic acinar cells, however, has not been studied, and understanding its mechanism could be crucial. We analysed plasma from 50 acute pancreatitis (AP) patients and 10 healthy donors using digital PCR, which links mitochondrial DNA (mtDNA) levels to the severity of AP. Single-cell sequencing of the pancreas during AP revealed differentially expressed genes and pathways in acinar cells. Experimental studies using mouse and cell models, which included mtDNA staining and quantitative PCR, revealed mtDNA leakage and the activation of STING-related pathways, indicating potential inflammatory mechanisms in AP. In conclusion, our study revealed that the mtDNA-STING-nuclear factor κB(NF-κB) pathway in pancreatic acinar cells could be a novel pathogenic factor in AP.
    Keywords:  Acute pancreatitis; Mitochondrial DNA; MtDNA-STING-NF-κB pathway; Pancreatic acinar cell injury
    DOI:  https://doi.org/10.1007/s10753-024-02132-0
  18. Am J Physiol Endocrinol Metab. 2024 Aug 28.
    Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human β-cells.
    Nayara Rampazzo Morelli, Camille Préfontaine, Jasmine Pipella, Peter J Thompson.
      Type 1 Diabetes (T1D) is a chronic metabolic disease resulting from autoimmune destruction of pancreatic beta cells. Beta cells activate a variety of stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D, therefore we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2L1. Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses.
    Keywords:  Cellular senescence; DNA damage response; GDF15; Pancreatic beta cells; Senescence associated secretory phenotype
    DOI:  https://doi.org/10.1152/ajpendo.00257.2024
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