bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒09‒17
ten papers selected by
Marco Tigano, Thomas Jefferson University
  1. PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
  2. Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response.
  3. Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
  4. Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
  5. Genome-Wide CRISPR/Cas9 Screening Identifies That Mitochondrial Solute Carrier SLC25A23 Attenuates Type I IFN Antiviral Immunity via Interfering with MAVS Aggregation.
  6. RatioCRISPR: A ratiometric biochip based on CRISPR/Cas12a for automated and multiplexed detection of heteroplasmic SNPs in mitochondrial DNA.
  7. Species-specific cleavage of cGAS by picornavirus protease 3C disrupts mitochondria DNA-mediated immune sensing.
  8. Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress.
  9. A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
  10. FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3β/GLI1 pathway.
  1. Front Cell Dev Biol. 2023 ;11 1270341
    PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
    Eva Rath.
      
    Keywords:  double-stranded RNA-activated protein kinase; doublestranded RNA; inflammatory bowel diseases; integrated stress response; mitochondria; mitochondrial unfolded protein response; proteostasis; stress signaling
    DOI:  https://doi.org/10.3389/fcell.2023.1270341
  2. bioRxiv. 2023 Sep 02. pii: 2023.09.01.555507. [Epub ahead of print]
    Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response.
    Agnes Karasik, Hernan A Lorenzi, Andrew V DePass, Nicholas R Guydosh.
      During viral infection, several dsRNA sensors are activated in the cell and trigger signaling that leads to changes in gene expression. One of these sensors activates an endonuclease, RNase L, that cleaves many types of RNA in the cell. However, how the resultant widespread RNA decay affects gene expression is not fully understood. Here we found that gene expression changes caused by activating dsRNA sensing pathways are tuned by RNase L activation, pointing to intricacy in the innate immune response where multiple inputs are integrated to create an optimized output. We show that RNase-L-dependent RNA fragmentation induces the activation of the Ribotoxic Stress Response, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L appears to limit the translation of genes that are regulated by another dsRNA-induced pathway, the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage events can directly evoke an antiviral program.Key summary: Activated RNase L acts together with other dsRNA-sensing pathways to induce a strong immune response via JNK and p38 signalingGeneric RNA fragmentation plays a key role in inducing transcription, potentially through ribosome collisionsActivation of RNase L inhibits the effects of eIF2α phosphorylationTranslation of the antiviral IFIT mRNAs is inhibited by active RNase L.
    DOI:  https://doi.org/10.1101/2023.09.01.555507
  3. Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):
    Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
    Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.
      Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202302091
  4. Dis Model Mech. 2023 Sep 11. pii: dmm.050114. [Epub ahead of print]
    Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency.
    Nicole M Sayles, Jill S Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi.
      Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion, YG8-800, KIKO-700, and FxnG127V. Few metabolites were changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.
    Keywords:  Cardiomyopathy; Frataxin; Friedreich Ataxia; Integrated stress response; Mitochondria; Mouse model
    DOI:  https://doi.org/10.1242/dmm.050114
  5. J Immunol. 2023 Sep 11. pii: ji2300187. [Epub ahead of print]
    Genome-Wide CRISPR/Cas9 Screening Identifies That Mitochondrial Solute Carrier SLC25A23 Attenuates Type I IFN Antiviral Immunity via Interfering with MAVS Aggregation.
    Hongguang Zhang, Xin Li, Yiwei Wang, Xianxian Liu, Jing Guo, Zheng Wang, Lulu Zhang, Sidong Xiong, Chunsheng Dong.
      Activation of the mitochondrial antiviral signaling (MAVS) adaptor, also known as IPS-1, VISA, or Cardif, is crucial for antiviral immunity in retinoic acid-inducible gene I (RIG-I)-like receptor signaling. Upon interacting with RIG-I, MAVS undergoes K63-linked polyubiquitination by the E3 ligase Trim31, and subsequently aggregates to activate downstream signaling effectors. However, the molecular mechanisms that modulate MAVS activation are not yet fully understood. In this study, the mitochondrial solute carrier SLC25A23 was found to attenuate type I IFN antiviral immunity using genome-wide CRISPR/Cas9 screening. SLC25A23 interacts with Trim31, interfering with its binding of Trim31 to MAVS. Indeed, SLC25A23 downregulation was found to increase K63-linked polyubiquitination and subsequent aggregation of MAVS, which promoted type I IFN production upon RNA virus infection. Consistently, mice with SLC25A23 knockdown were more resistant to RNA virus infection in vivo. These findings establish SLC25A23 as a novel regulator of MAVS posttranslational modifications and of type I antiviral immunity.
    DOI:  https://doi.org/10.4049/jimmunol.2300187
  6. Biosens Bioelectron. 2023 Sep 09. pii: S0956-5663(23)00618-8. [Epub ahead of print]241 115676
    RatioCRISPR: A ratiometric biochip based on CRISPR/Cas12a for automated and multiplexed detection of heteroplasmic SNPs in mitochondrial DNA.
    Xiaolong Wu, Yi Zhao, Chuanghao Guo, Conghui Liu, Qianling Zhang, Yong Chen, Yizhen Liu, Xueji Zhang.
      Mitochondrial genetic diseases are often characterized by heteroplasmic single nucleotide polymorphisms (SNPs) where both wild-type (WT) and mutant-type (MT) coexist, making detection of accurate SNP abundance critical for diagnosis. Here, we present RatioCRISPR, an automated ratiometric biochip sensor based on the CRISPR/Cas12a system for detecting multiple heteroplasmic SNPs in mitochondrial DNA (mtDNA). The ratiometric sensor output is only influenced by the relative abundance of WT and MT, with minimal impact from sample concentration. Biochips allow the simultaneous detection of multiple SNP sites for more accurate disease diagnosis. RatioCRISPR can accurately detect 8 samples simultaneously within 25 min with a limit of detection (LOD) of 15.7 aM. We successfully detected 13 simulated samples of three mtDNA point mutations (m.3460G>A, m.11778G>A, and m.14484T>C), which lead to Leber's hereditary optic neuropathy (LHON) and set a threshold (60%) of heteroplasmy to evaluate disease risk. This automated and accurate biosensor has broad applications in diagnosing multiple SNPs, especially those with heteroplasmic variations, making it an advanced and convenient tool for mtDNA disease diagnosis.
    DOI:  https://doi.org/10.1016/j.bios.2023.115676
  7. PLoS Pathog. 2023 Sep 14. 19(9): e1011641
    Species-specific cleavage of cGAS by picornavirus protease 3C disrupts mitochondria DNA-mediated immune sensing.
    Ya Yan, Lei Wu, Ye Yuan, Haiwei Wang, Hongyan Yin, Minjie Li, Lvye Chai, Ruiying Liang, Yanjie Liu, Dongming Zhao, Junji Xing, Pingwei Li, Xin Li.
      RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA) mediated activation. However, the mechanisms of cGAS mediated innate immune evasion by RNA viruses remain unknown. Here, we report that seneca valley virus (SVV) protease 3C disrupts mtDNA mediated innate immune sensing by cleaving porcine cGAS (pcGAS) in a species-specific manner. Mechanistically, a W/Q motif within the N-terminal domain of pcGAS is a unique cleavage site recognized by SVV 3C. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS, but not human cGAS (hcGAS) or mouse cGAS (mcGAS). Additionally, upon SVV infection and poly(dA:dT) transfection, pcGAS and SVV 3C colocalizes in the cells. Furthermore, SVV 3C disrupts pcGAS-mediated DNA binding, cGAMP synthesis and interferon induction by specifically cleaving pcGAS. This work uncovers a novel mechanism by which the viral protease cleaves the DNA sensor cGAS to evade innate immune response, suggesting a new antiviral approaches against picornaviruses.
    DOI:  https://doi.org/10.1371/journal.ppat.1011641
  8. Cell Death Discov. 2023 Sep 11. 9(1): 340
    Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress.
    Trinh T T Phan, Nam V Truong, Wen-Guey Wu, Yi-Chun Su, Tzu-Sheng Hsu, Lih-Yuan Lin.
      The tumor suppressor p53 primarily functions as a mediator of DNA damage-induced cell death, thereby contributing to the efficacy of genotoxic anticancer therapeutics. Here, we show, on the contrary, that cancer cells can employ genotoxic stress-induced p53 to acquire treatment resistance through the production of the pleiotropic cytokine interleukin (IL)-6. Mechanistically, DNA damage, either repairable or irreparable, activates p53 and stimulates Caspase-2-mediated cleavage of its negative regulator mouse double minute 2 (MDM2) creating a positive feedback loop that leads to elevated p53 protein accumulation. p53 transcriptionally controls the major adenosine triphosphate (ATP) release channel pannexin 1 (Panx1), which directs IL-6 induction via a mechanism dependent on the extracellular ATP-activated purinergic P2 receptors as well as their downstream intracellular calcium (iCa2+)/PI3K/Akt/NF-ĸB signaling pathway. Thus, p53 silencing impairs Panx1 and IL-6 expression and renders cancer cells sensitive to genotoxic stress. Moreover, we confirm that IL-6 hampers the effectiveness of genotoxic anticancer agents by mitigating DNA damage, driving the expression of anti-apoptotic Bcl-2 family genes, and maintaining the migratory and invasive properties of cancer cells. Analysis of patient survival and relevant factors in lung cancer and pan-cancer cohorts supports the prognostic and clinical values of Panx1 and IL-6. Notably, IL-6 secreted by cancer cells during genotoxic treatments promotes the polarization of monocytic THP-1-derived macrophages into an alternative (M2-like) phenotype that exhibits impaired anti-survival activities but enhanced pro-metastatic effects on cancer cells as compared to nonpolarized macrophages. Our study reveals the precise mechanism for genotoxic-induced IL-6 and suggests that targeting p53-mediated IL-6 may improve the responsiveness of cancer cells to genotoxic anticancer therapy.
    DOI:  https://doi.org/10.1038/s41420-023-01638-0
  9. Cell Rep. 2023 Sep 12. pii: S2211-1247(23)01044-6. [Epub ahead of print]42(9): 113033
    A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
    C Dilanka Fernando, W Samantha N Jayasekara, Chaitanya Inampudi, Maija R J Kohonen-Corish, Wendy A Cooper, Traude H Beilharz, Tracy M Josephs, Daniel J Garama, Daniel J Gough.
      Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.
    Keywords:  CP: Cancer; CP: Molecular biology; LRPPRC; SLIRP; STAT3; lung adenocarcinoma; mRNA stability; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.113033
  10. Acta Biochim Biophys Sin (Shanghai). 2023 Sep 12.
    FUNDC2, a mitochondrial outer membrane protein, mediates triple-negative breast cancer progression via the AKT/GSK3β/GLI1 pathway.
    Liyang Yin, Renxian Cao, Zhuoqing Liu, Gang Luo, Yu Li, Xiaolong Zhou, Xiguang Chen, Ying Wu, Jun He, Xuyu Zu, Yingying Shen.
      Triple-negative breast cancer (TNBC) lacks effective therapeutic targets and has a poor prognosis, easy recurrence and metastasis. It is urgent and important to explore TNBC treatment targets. Through mass spectrometry combined with qRT-PCR validation in luminal A cells and TNBC cells, high-content screening and clinical sample analysis, FUNDC2 was discovered as a novel target. The function of the outer mitochondrial membrane protein FUNDC2 in breast cancer is still unclear. In this study, we find that FUNDC2 expression in TNBC tissues is significantly higher than that in luminal subtype breast cancer tissues. FUNDC2 silencing in TNBC cells significantly reduces cell proliferation, migration and invasion. As demonstrated in vivo using subcutaneous tumor xenografts in mice, FUNDC2 suppression significantly inhibits tumor growth. The underlying mechanism might be mediated by inactivating its downstream signal AKT/GSK3β and GLI1, a key factor of the Hedgehog signaling pathway. Therefore, FUNDC2 may promote TNBC progression and provide a therapeutic target for treating TNBC.
    Keywords:  FUNDC2; GLI1; therapeutic target; triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3724/abbs.2023142
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒16 at 15:42.