bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024‒01‒28
thirteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Yeast EndoG prevents genome instability by degrading cytoplasmic DNA.
  2. XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
  3. Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
  4. Regulation of nuclear transcription by mitochondrial RNA in endothelial cells.
  5. Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.
  6. Inflammatory Cytokines Can Induce Synthesis Of Type-I Interferon.
  7. Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling.
  8. Mitochondrial translocation of TFEB regulates complex I and inflammation.
  9. Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
  10. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
  11. Mitochondria-Associated Transcriptome Profiling via Localizable Aggregation-Induced Emission Photosensitizers in Live Cells.
  12. Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number.
  13. Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation.
  1. Res Sq. 2024 Jan 05. pii: rs.3.rs-3641411. [Epub ahead of print]
    Yeast EndoG prevents genome instability by degrading cytoplasmic DNA.
    Grzegorz Ira, Yang Yu, Xin Wang, Jordan Fox, Ruofan Yu, Brenna McCauley, Nic Nikoloutsos, Qian Li, Philip Hastings, Weiwei Dang, Kaifu Chen, Pilendra Thakre.
      In metazoans release of mitochondrial DNA or retrotransposon cDNA to cytoplasm can cause sterile inflammation and disease 1. Cytoplasmic nucleases degrade these DNA species to limit inflammation 2,3. It remains unknown whether degradation these DNA also prevents nuclear genome instability. To address this question, we decided to identify the nuclease regulating transfer of these cytoplasmic DNA species to the nucleus. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products. Nuclear mtDNA (NUMTs) and retrotransposon cDNA insertions increase dramatically in nondividing stationary phase cells. Yeast EndoG (Nuc1) nuclease limits insertions of cDNA and transfer of very long mtDNA (>10 kb) that forms unstable circles or rarely insert in the genome, but it promotes formation of short NUMTs (~45-200 bp). Nuc1 also regulates transfer of cytoplasmic DNA to nucleus in aging or during meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs can originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating cytoplasmic DNA play a role in preserving genome stability.
    DOI:  https://doi.org/10.21203/rs.3.rs-3641411/v1
  2. Cell Rep. 2024 Jan 22. pii: S2211-1247(23)01612-1. [Epub ahead of print]43(2): 113600
    XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
    Tao Zou, Meng Zhou, Akansha Gupta, Patrick Zhuang, Alyssa R Fishbein, Hope Y Wei, Diego Capcha-Rodriguez, Zhouwei Zhang, Andrew D Cherniack, Matthew Meyerson.
      Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.
    Keywords:  CP: Cancer; CP: Immunology; PKR; RNA sensing; XRN1; cancer; interferon
    DOI:  https://doi.org/10.1016/j.celrep.2023.113600
  3. Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13
    Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
    Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.
      Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.
    Keywords:  D. melanogaster; S. cerevisiae; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.84282
  4. Elife. 2024 Jan 22. pii: e86204. [Epub ahead of print]13
    Regulation of nuclear transcription by mitochondrial RNA in endothelial cells.
    Kiran Sriram, Zhijie Qi, Dongqiang Yuan, Naseeb Kaur Malhi, Xuejing Liu, Riccardo Calandrelli, Yingjun Luo, Alonso Tapia, Shengyan Jin, Ji Shi, Martha Salas, Runrui Dang, Brian Armstrong, Saul J Priceman, Ping H Wang, Jiayu Liao, Rama Natarajan, Sheng Zhong, Zhen Bouman Chen.
      Chromatin-associated RNAs (caRNAs) form a relatively poorly recognized layer of the epigenome. The caRNAs reported to date are transcribed from the nuclear genome. Here, leveraging a recently developed assay for detection of caRNAs and their genomic association, we report that mitochondrial RNAs (mtRNAs) are attached to the nuclear genome and constitute a subset of caRNA, thus termed mt-caRNA. In four human cell types analyzed, mt-caRNAs preferentially attach to promoter regions. In human endothelial cells (ECs), the level of mt-caRNA-promoter attachment changes in response to environmental stress that mimics diabetes. Suppression of a non-coding mt-caRNA in ECs attenuates stress-induced nascent RNA transcription from the nuclear genome, including that of critical genes regulating cell adhesion, and abolishes stress-induced monocyte adhesion, a hallmark of dysfunctional ECs. Finally, we report increased nuclear localization of multiple mtRNAs in the ECs of human diabetic donors, suggesting many mtRNA translocate to the nucleus in a cell stress and disease-dependent manner. These data nominate mt-caRNAs as messenger molecules responsible for mitochondrial-nuclear communication and connect the immediate product of mitochondrial transcription with the transcriptional regulation of the nuclear genome.
    Keywords:  chromatin; chromosomes; diabetes; endothelial cells; gene expression; human; immunology; inflammation; innate immunity; lncRNA; mitochondrial RNA; nucleus; transcription
    DOI:  https://doi.org/10.7554/eLife.86204
  5. Cell Rep. 2024 Jan 22. pii: S2211-1247(24)00012-3. [Epub ahead of print]43(2): 113684
    Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.
    Amir Hosseini, Håvard T Lindholm, Raymond Chen, Parinaz Mehdipour, Sajid A Marhon, Charles A Ishak, Paul C Moore, Marie Classon, Andrea Di Gioacchino, Benjamin Greenbaum, Daniel D De Carvalho.
      Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.
    Keywords:  CP: Cancer; CP: Immunology; XRN1; endogenous retroelements; viral mimicry
    DOI:  https://doi.org/10.1016/j.celrep.2024.113684
  6. bioRxiv. 2024 Jan 08. pii: 2024.01.08.574713. [Epub ahead of print]
    Inflammatory Cytokines Can Induce Synthesis Of Type-I Interferon.
    Nikhil Sharma, Xu Qi, Patricia Kessler, Ganes C Sen.
      Type I interferon (IFN) is induced in virus infected cells, secreted and it inhibits viral replication in neighboring cells. IFN is also an important player in many non-viral diseases and in the development of normal immune cells. Although the signaling pathways for IFN induction by viral RNA or DNA have been extensively studied, its mode of induction in uninfected cells remains obscure. Here, we report that inflammatory cytokines, such as TNF-α and IL-1β, can induce IFN-β through activation of the cytoplasmic RIG-I signaling pathway. However, RIG-I is activated not by RNA, but by PACT, the protein activator of PKR. In cell lines or primary cells expressing RIG-I and PACT, activation of the MAPK, p38, by cytokine signaling, leads to phosphorylation of PACT, which binds to primed RIG-I and activates its signaling pathway. Thus, a new mode of type I IFN induction by ubiquitous inflammatory cytokines has been revealed.Key points: Cytochalasin D followed by TNF-α / IL-1β treatment activates IFN-β expression.IFN-β expression happens due to activation of RIG-I signaling.Interaction between RIG-I and PACT activates IFN-β expression.
    DOI:  https://doi.org/10.1101/2024.01.08.574713
  7. bioRxiv. 2024 Jan 04. pii: 2024.01.04.574136. [Epub ahead of print]
    Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling.
    Abraham Shim, Xiaohan Luan, Wen Zhou, Yanick Crow, John Maciejowski.
      The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations - particularly those outside of the core catalytic domains - remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupt TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenous TREX1 locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization.
    DOI:  https://doi.org/10.1101/2024.01.04.574136
  8. EMBO Rep. 2024 Jan 23.
    Mitochondrial translocation of TFEB regulates complex I and inflammation.
    Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.
      TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.
    Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB
    DOI:  https://doi.org/10.1038/s44319-024-00058-0
  9. Nature. 2024 Jan 24.
    Motion of VAPB molecules reveals ER-mitochondria contact site subdomains.
    Christopher J Obara, Jonathon Nixon-Abell, Andrew S Moore, Federica Riccio, David P Hoffman, Gleb Shtengel, C Shan Xu, Kathy Schaefer, H Amalia Pasolli, Jean-Baptiste Masson, Harald F Hess, Christopher P Calderon, Craig Blackstone, Jennifer Lippincott-Schwartz.
      To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites1,2. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites3,4. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle5,6. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation7,8, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.
    DOI:  https://doi.org/10.1038/s41586-023-06956-y
  10. Nat Aging. 2024 Jan 24.
    TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
    Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang.
      Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1-cGAS interaction is a relevant target for selectively suppressing inflammaging.
    DOI:  https://doi.org/10.1038/s43587-023-00564-1
  11. ACS Chem Biol. 2024 Jan 24.
    Mitochondria-Associated Transcriptome Profiling via Localizable Aggregation-Induced Emission Photosensitizers in Live Cells.
    Jiying Liang, Jinghua Han, Yuan Zhuang, GuanHua Chen, Ying Li.
      In recent decades, there has been increasing interest in studying mitochondria through transcriptomic research. Various exogenous fusion protein-based proximity labeling methods have been reported that focus on the site of one particular protein/peptide and might also influence the corresponding localization or interactome. To enable unbiased and high spatial-resolution profiling of mitochondria-associated transcriptomes in live cells, a flexible RNA proximity labeling approach was developed using aggregation-induced emission (AIE) type photosensitizers (PSs) that possess great mitochondria-targeting capabilities. Their accumulation in an enclosed mitochondrial environment tends to enhance the fluorescence emission and reactive oxygen species generation. By comparing the in vitro optical properties, photosensitization processes, as well as the in cellulo mitochondrial specificity and RNA labeling performance of four AIE PSs, high-throughput sequencing analysis was conducted using TFPy-mediated RNA proximity labeling in live HeLa cells. This approach successfully captured a comprehensive list of transcripts, including mitochondria-encoded RNAs, as well as some nuclear-derived RNAs located at the outer mitochondrial membrane and interacting organelles. This small molecule-based proximity labeling method bypasses complex genetic manipulation and transfection steps, making it readily applicable for diverse research purposes.
    DOI:  https://doi.org/10.1021/acschembio.3c00617
  12. Sci Rep. 2024 01 24. 14(1): 2083
    Nuclear and mitochondrial genetic variants associated with mitochondrial DNA copy number.
    Adriana Koller, Michele Filosi, Hansi Weissensteiner, Federica Fazzini, Mathias Gorski, Cristian Pattaro, Sebastian Schönherr, Lukas Forer, Janina M Herold, Klaus J Stark, Patricia Döttelmayer, Andrew A Hicks, Peter P Pramstaller, Reinhard Würzner, Kai-Uwe Eckardt, Iris M Heid, Christian Fuchsberger, Claudia Lamina, Florian Kronenberg.
      Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10-13) and GSDMA (rs56030650, p = 4.85 × 10-08) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.
    DOI:  https://doi.org/10.1038/s41598-024-52373-0
  13. bioRxiv. 2024 Jan 04. pii: 2024.01.03.574059. [Epub ahead of print]
    Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation.
    L Peruzzotti-Jametti, C M Willis, R Hamel, G Krzak, J A Reisz, H A Prag, V Wu, Y Xiang, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, A E Vincent, C Frezza, C Viscomi, J C Marioni, A D'Alessandro, Z Takats, M P Murphy, S Pluchino.
      Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis (MS) 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . However, how these metabolic features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identified a new molecular signature that perpetuates the activation of myeloid cells through mitochondrial complex II (CII) and I (CI) activity driving reverse electron transport (RET) and the production of reactive oxygen species (ROS). Blocking RET in pro-inflammatory myeloid cells protected the central nervous system (CNS) against neurotoxic damage and improved functional outcomes in animal disease models in vivo . Our data show that RET in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory CNS disorders 3 .
    DOI:  https://doi.org/10.1101/2024.01.03.574059
This page is being maintained by Thomas Krichel. It was last updated on 2024‒01‒28 at 18:34.