bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–07–23
eleven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Mitochondrial double-stranded RNA triggers induction of the antiviral DNA deaminase APOBEC3A and nuclear DNA damage.
  2. Hypoxia-induced mitochondrial stress granules.
  3. Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
  4. Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape.
  5. ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.
  6. The role of protein kinase R in placental inflammation, mtUPR and apoptosis.
  7. RIG-I-like receptors: Molecular mechanism of activation and signaling.
  8. Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.
  9. Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
  10. Radiation therapy-induced neurocognitive impairment is driven by heightened apoptotic priming in early life and prevented by blocking BAX.
  11. Amplifying antitumor immunity with iPSC-derived exosomes.
  1. J Biol Chem. 2023 Jul 18. pii: S0021-9258(23)02101-4. [Epub ahead of print] 105073
    Mitochondrial double-stranded RNA triggers induction of the antiviral DNA deaminase APOBEC3A and nuclear DNA damage.
    Chloe Wick, Seyed Arad Moghadasi, Jordan T Becker, Elisa Fanunza, Sunwoo Oh, Elodie Bournique, Rémi Buisson, Reuben S Harris.
      APOBEC3A is an antiviral DNA deaminase often induced by virus infection. APOBEC3A is also a source of cancer mutation in viral and non-viral tumor types. It is therefore critical to identify factors responsible for APOBEC3A upregulation. Here, we test the hypothesis that leaked mitochondrial (mt) double-stranded (ds)RNA is recognized as foreign nucleic acid, which triggers innate immune signaling, APOBEC3A upregulation, and DNA damage. Knockdown of an enzyme responsible for degrading mtdsRNA, the exoribonuclease polynucleotide phosphorylase (PNPase), results in mtdsRNA leakage into the cytosol and induction of APOBEC3A expression. APOBEC3A upregulation by cytoplasmic mtdsRNA requires RIG-I, MAVS, and STAT2 and is likely part of a broader type I interferon response. Importantly, although mtdsRNA-induced APOBEC3A appears cytoplasmic by subcellular fractionation experiments, its induction triggers an overt DNA damage response characterized by elevated nuclear γ-H2AX staining. Thus, mtdsRNA dysregulation may induce APOBEC3A and contribute to observed genomic instability and mutation signatures in cancer.
    Keywords:  APOBEC3A; DNA damage response; cancer mutagenesis; innate immune signaling; mitochondrial dsRNA
    DOI:  https://doi.org/10.1016/j.jbc.2023.105073
  2. Cell Death Dis. 2023 Jul 19. 14(7): 448
    Hypoxia-induced mitochondrial stress granules.
    Chun-Ling Sun, Marc Van Gilst, C Michael Crowder.
      Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.
    DOI:  https://doi.org/10.1038/s41419-023-05988-6
  3. Front Genet. 2023 ;14 1089956
    Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
    Chiara Frascarelli, Nadia Zanetti, Alessia Nasca, Rossella Izzo, Costanza Lamperti, Eleonora Lamantea, Andrea Legati, Daniele Ghezzi.
      Primary mitochondrial diseases are progressive genetic disorders affecting multiple organs and characterized by mitochondrial dysfunction. These disorders can be caused by mutations in nuclear genes coding proteins with mitochondrial localization or by genetic defects in the mitochondrial genome (mtDNA). The latter include point pathogenic variants and large-scale deletions/rearrangements. MtDNA molecules with the wild type or a variant sequence can exist together in a single cell, a condition known as mtDNA heteroplasmy. MtDNA single point mutations are typically detected by means of Next-Generation Sequencing (NGS) based on short reads which, however, are limited for the identification of structural mtDNA alterations. Recently, new NGS technologies based on long reads have been released, allowing to obtain sequences of several kilobases in length; this approach is suitable for detection of structural alterations affecting the mitochondrial genome. In the present work we illustrate the optimization of two sequencing protocols based on long-read Oxford Nanopore Technology to detect mtDNA structural alterations. This approach presents strong advantages in the analysis of mtDNA compared to both short-read NGS and traditional techniques, potentially becoming the method of choice for genetic studies on mtDNA.
    Keywords:  MinION; complex-rearrangements; long reads; macrodeletion; mtDNA; multiple deletions; oxford nanopore; structural variants
    DOI:  https://doi.org/10.3389/fgene.2023.1089956
  4. Cell Syst. 2023 Jul 19. pii: S2405-4712(23)00154-0. [Epub ahead of print]14(7): 551-562.e5
    Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape.
    Taivan Batjargal, Francesca Zappa, Ryan J Grant, Robert A Piscopio, Alex Chialastri, Siddharth S Dey, Diego Acosta-Alvear, Maxwell Z Wilson.
      The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  Cryptochrome 2; RNA-seq; cellular resilience; integrated stress response; optogenetics; stress memory landscape; systems biology
    DOI:  https://doi.org/10.1016/j.cels.2023.06.001
  5. Nat Cell Biol. 2023 Jul 17.
    ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.
    Chuan-Yang Dai, Chai Chee Ng, Grace Ching Ching Hung, Ina Kirmes, Laetitia A Hughes, Yunguang Du, Christopher A Brosnan, Arnaud Ahier, Anne Hahn, Cole M Haynes, Oliver Rackham, Aleksandra Filipovska, Steven Zuryn.
      The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.
    DOI:  https://doi.org/10.1038/s41556-023-01192-y
  6. Placenta. 2023 Jul 11. pii: S0143-4004(23)00157-1. [Epub ahead of print]139 200-211
    The role of protein kinase R in placental inflammation, mtUPR and apoptosis.
    Umut Kerem Kolac, Gizem Donmez Yalcin, Ramazan Karayel, Abdullah Yalcin.
       INTRODUCTION: Placental inflammation is implicated in the pathophysiology of many pregnancy complications, including fetal growth restriction, preeclampsia, gestational diabetes, and choriocarcinoma. Mitochondrial dysfunction, one of the outcomes of placental inflammation, is characterized by loss of membrane potential, accumulation of oxygen radicals, mitochondrial protein folding defects, and disturbances in mitochondrial dynamics. Protein kinase R (PKR) is stimulated by double-stranded RNA and bacterial endotoxins in the presence of pathogens and is a critical immune response enzyme. PKR is also correlated with the cell death response during endoplasmic reticulum stress. In this study, we aim to investigate the effects of PKR activity stimulated by lipopolysaccharide (LPS), and double-stranded RNA analog (Poly I:C) on mitochondrial unfolded protein response (mtUPR), mitochondrial membrane potential, apoptosis, and oxidative stress in placental trophoblasts.
    METHODS: We applied LPS and Poly I:C to BeWo cells to induce PKR activation. In addition, cells were treated with 2-aminopurine (2-AP) to inhibit the kinase activity of PKR. Protein levels of ATP-dependent Clp protease proteolytic subunit (CLPP) and heat shock protein 60 (HSP60) were determined after treatments. Apoptotic markers were detected by real-time PCR and flow cytometry. PKR-induced reactive oxygen radicals (ROS) accumulation and mitochondrial membrane potential change were assessed by flow cytometry.
    RESULTS: It was determined that PKR activation-induced apoptosis in BeWo cells by reducing the levels of mtUPR proteins (CLPP and HSP60) and caused a decrease in mitochondrial membrane potential. PKR inhibition was sufficient for decreases in apoptotic markers and caused a reduction in the ratio of depolarized and ROS (+) cells.
    DISCUSSION: Our results showed that LPS and Poly I:C administration stimulated PKR in BeWo cells in vitro. Furthermore, PKR activation is correlated with the levels of proteins involved in mitochondrial homeostasis and apoptosis. Our findings will contribute to understanding the role of PKR activation in placental inflammation and related diseases.
    Keywords:  Apoptosis; Mitochondrial membrane potential; PKR; mtUPR
    DOI:  https://doi.org/10.1016/j.placenta.2023.07.007
  7. Adv Immunol. 2023 ;pii: S0065-2776(23)00002-0. [Epub ahead of print]158 1-74
    RIG-I-like receptors: Molecular mechanism of activation and signaling.
    Jie Zheng, Wenjia Shi, Ziqun Yang, Jin Chen, Ao Qi, Yulin Yang, Ying Deng, Dongyuan Yang, Ning Song, Bin Song, Dahai Luo.
      During RNA viral infection, RIG-I-like receptors (RLRs) recognize the intracellular pathogenic RNA species derived from viral replication and activate antiviral innate immune response by stimulating type 1 interferon expression. Three RLR members, namely, RIG-I, MDA5, and LGP2 are homologous and belong to a subgroup of superfamily 2 Helicase/ATPase that is preferably activated by double-stranded RNA. RLRs are significantly different in gene architecture, RNA ligand preference, activation, and molecular functions. As switchable macromolecular sensors, RLRs' activities are tightly regulated by RNA ligands, ATP, posttranslational modifications, and cellular cofactors. We provide a comprehensive review of the structure and function of the RLRs and summarize the molecular understanding of sensing and signaling events during the RLR activation process. The key roles RLR signaling play in both anti-infection and immune disease conditions highlight the therapeutic potential in targeting this important molecular pathway.
    Keywords:  Antiviral innate immunity; Autoimmune diseases; RNA helicase; Structural biology; Virus infection
    DOI:  https://doi.org/10.1016/bs.ai.2023.03.001
  8. Nat Commun. 2023 07 19. 14(1): 4360
    Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.
    Shubhi Srivastava, Priyanka Gajwani, Jordan Jousma, Hiroe Miyamoto, Youjeong Kwon, Arundhati Jana, Peter T Toth, Gege Yan, Sang-Ging Ong, Jalees Rehman.
      Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo. The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury.
    DOI:  https://doi.org/10.1038/s41467-023-40084-5
  9. Autophagy. 2023 Jul 16.
    Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
    Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Nobuo N Noda, Tomotake Kanki.
      Mitophagy is a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation. During mitophagy, specific selective autophagy receptors (SARs) mark a portion of mitochondria to recruit the autophagy-related (Atg) machinery and nucleate a phagophore. The phagophore expands and surrounds the mitochondrial cargo, forming an autophagosome. Fission plays a crucial role in separating the targeted portion of mitochondria from the main body to sequester it within the autophagosome. Our recent study, utilizing fission and budding yeasts as model systems, has identified Atg44 as a mitochondrial fission factor that generates mitochondrial fragments suitable for phagophore engulfment. Atg44 resides in the mitochondrial intermembrane space (IMS) and interacts with lipid membranes, with the capacity of mediating membrane fragility and fission. Based on our findings, we propose the term mitofissin to refer to Atg44 and its homologous proteins, which might participate in diverse cellular processes requiring membrane remodeling across various species.
    Keywords:  Atg44; autophagy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast
    DOI:  https://doi.org/10.1080/15548627.2023.2237343
  10. Cancer Res. 2023 Jul 20. pii: CAN-22-1337. [Epub ahead of print]
    Radiation therapy-induced neurocognitive impairment is driven by heightened apoptotic priming in early life and prevented by blocking BAX.
    Rumani Singh, Stacey Yu, Marwa Osman, Zintis Inde, Cameron Fraser, Abigail H Cleveland, Nicole Almanzar, Chuan Bian Lim, Gaurav N Joshi, Johan Spetz, Xingping Qin, Sneh M Toprani, Zachary Nagel, Matthew C Hocking, Robert A Cormack, Torunn I Yock, Jeffrey W Miller, Zhi-Min Yuan, Timothy Gershon, Kristopher A Sarosiek.
      Although external beam radiation therapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histological analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single cell RNA-seq data revealed that neural cell vulnerability stems from heightened expression of pro-apoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, pro-apoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by pro-apoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. Based on these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM or BID via direct or upstream mechanisms is expected to ameliorate neurocognitive impairment in pediatric CNS tumor patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1337
  11. Mol Ther. 2023 Jul 18. pii: S1525-0016(23)00382-9. [Epub ahead of print]
    Amplifying antitumor immunity with iPSC-derived exosomes.
    Quazi T H Shubhra, Peter Veranič, Zhenming Wang.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2023.07.001
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