bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–08–20
thirteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Sublethal engagement of apoptotic pathways in residual cancer.
  2. An unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes.
  3. Deoxyribonucleoside treatment rescues EtBr-induced mtDNA depletion in iPSC-derived neural stem cells with POLG mutations.
  4. E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
  5. XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.
  6. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.
  7. NME3 binds to phosphatidic acid and mediates PLD6-induced mitochondrial tethering.
  8. Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells.
  9. Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.
  10. MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation.
  11. A conserved family of immune effectors cleaves cellular ATP upon viral infection.
  12. Machine learning predicts cellular response to genetic perturbation.
  13. Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels.
  1. Trends Cell Biol. 2023 Aug 10. pii: S0962-8924(23)00138-1. [Epub ahead of print]
    Sublethal engagement of apoptotic pathways in residual cancer.
    Shane T Killarney, Stephen W G Tait, Douglas R Green, Kris C Wood.
      Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).
    Keywords:  DNA damage response; drug-tolerant persisters; integrated stress response; sublethal MOMP
    DOI:  https://doi.org/10.1016/j.tcb.2023.07.005
  2. bioRxiv. 2023 Aug 03. pii: 2023.08.03.551696. [Epub ahead of print]
    An unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes.
    Simone Caielli, Preetha Balasubramanian, Juan Rodriguez-Alcazar, Uthra Balaji, Zurong Wan, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Djamel Nehar-Belaid, Radu Marches, Lorien Nassi, Katie Stewart, Julie Fuller, Jacques F Banchereau, Jinghua Gu, Tracey Wright, Virginia Pascual.
      Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.
    DOI:  https://doi.org/10.1101/2023.08.03.551696
  3. FASEB J. 2023 09;37(9): e23139
    Deoxyribonucleoside treatment rescues EtBr-induced mtDNA depletion in iPSC-derived neural stem cells with POLG mutations.
    Cecilie Katrin Kristiansen, Jessica Furriol, Anbin Chen, Gareth John Sullivan, Laurence A Bindoff, Kristina Xiao Liang.
      Mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (Pol-γ), lead to diseases driven by defective mtDNA maintenance. Despite being the most prevalent cause of mitochondrial disease, treatments for POLG-related disorders remain elusive. In this study, we used POLG patient-induced pluripotent stem cell (iPSC)-derived neural stem cells (iNSCs), one homozygous for the POLG mutation c.2243G>C and one compound heterozygous with c.2243G>C and c.1399G>A, and treated these iNSCs with ethidium bromide (EtBr) to study the rate of depletion and repopulation of mtDNA. In addition, we investigated the effect of deoxyribonucleoside (dNs) supplementation on mtDNA maintenance during EtBr treatment and post-treatment repopulation in the same cells. EtBr-induced mtDNA depletion occurred at a similar rate in both patient and control iNSCs, however, restoration of mtDNA levels was significantly delayed in iNSCs carrying the compound heterozygous POLG mutations. In contrast, iNSC with the homozygous POLG mutation recovered their mtDNA at a rate similar to controls. When we treated cells with dNs, we found that this reduced EtBr-induced mtDNA depletion and significantly increased repopulation rates in both patient iNSCs. These observations are consistent with the hypothesis that mutations in POLG impair mtDNA repopulation also within intact neural lineage cells and suggest that those with compound heterozygous mutation have a more severe defect of mtDNA synthesis. Our findings further highlight the potential for dNs to improve mtDNA replication in the presence of POLG mutations, suggesting that this may offer a new therapeutic modality for mitochondrial diseases caused by disturbed mtDNA homeostasis.
    Keywords:  deoxynucleosides; iPSCs; mitochondrial DNA replication; neural stem cells; polymerase γ; therapy
    DOI:  https://doi.org/10.1096/fj.202300650RR
  4. Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00563-4. [Epub ahead of print]83(16): 2976-2990.e9
    E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.
    Vincent Anton, Ira Buntenbroich, Tânia Simões, Mariana Joaquim, Leonie Müller, Reinhard Buettner, Margarete Odenthal, Thorsten Hoppe, Mafalda Escobar-Henriques.
      Ubiquitin-dependent control of mitochondrial dynamics is important for protein quality and neuronal integrity. Mitofusins, mitochondrial fusion factors, can integrate cellular stress through their ubiquitylation, which is carried out by multiple E3 enzymes in response to many different stimuli. However, the molecular mechanisms that enable coordinated responses are largely unknown. Here we show that yeast Ufd2, a conserved ubiquitin chain-elongating E4 enzyme, is required for mitochondrial shape adjustments. Under various stresses, Ufd2 translocates to mitochondria and triggers mitofusin ubiquitylation. This elongates ubiquitin chains on mitofusin and promotes its proteasomal degradation, leading to mitochondrial fragmentation. Ufd2 and its human homologue UBE4B also target mitofusin mutants associated with Charcot-Marie-Tooth disease, a hereditary sensory and motor neuropathy characterized by progressive loss of the peripheral nerves. This underscores the pathophysiological importance of E4-mediated ubiquitylation in neurodegeneration. In summary, we identify E4-dependent mitochondrial stress adaptation by linking various metabolic processes to mitochondrial fusion and fission dynamics.
    Keywords:  CMT2A; Cdc48/p97; E4; Fzo1; MFN2; UBE4B; Ufd2; fusion; mitochondria; mitofusin; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.021
  5. bioRxiv. 2023 Aug 03. pii: 2023.08.01.551488. [Epub ahead of print]
    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, 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 (ISG) expression. XRN1 deletion causes PKR 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 nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.
    DOI:  https://doi.org/10.1101/2023.08.01.551488
  6. Nature. 2023 Aug 16.
    Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.
    Rahul Gupta, Masahiro Kanai, Timothy J Durham, Kristin Tsuo, Jason G McCoy, Anna V Kotrys, Wei Zhou, Patrick F Chinnery, Konrad J Karczewski, Sarah E Calvo, Benjamin M Neale, Vamsi K Mootha.
      Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.
    DOI:  https://doi.org/10.1038/s41586-023-06426-5
  7. J Cell Biol. 2023 10 02. pii: e202301091. [Epub ahead of print]222(10):
    NME3 binds to phosphatidic acid and mediates PLD6-induced mitochondrial tethering.
    You-An Su, Hsin-Yi Chiu, Yu-Chen Chang, Chieh-Ju Sung, Chih-Wei Chen, Reika Tei, Xuang-Rong Huang, Shao-Chun Hsu, Shan-Shan Lin, Hsien-Chu Wang, Yu-Chun Lin, Jui-Cheng Hsu, Hermann Bauer, Yuxi Feng, Jeremy M Baskin, Zee-Fen Chang, Ya-Wen Liu.
      Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is particularly crucial for the function and quality control of mitochondria. Phosphatidic acid (PA) on the mitochondrial outer membrane generated by PLD6 facilitates the fusion of mitochondria. However, how PA promotes mitochondrial fusion remains unclear. Here, we show that a mitochondrial outer membrane protein, NME3, is required for PLD6-induced mitochondrial tethering or clustering. NME3 is enriched at the contact interface of two closely positioned mitochondria depending on PLD6, and NME3 binds directly to PA-exposed lipid packing defects via its N-terminal amphipathic helix. The PA binding function and hexamerization confer NME3 mitochondrial tethering activity. Importantly, nutrient starvation enhances the enrichment efficiency of NME3 at the mitochondrial contact interface, and the tethering ability of NME3 contributes to fusion efficiency. Together, our findings demonstrate NME3 as a tethering protein promoting selective fusion between PLD6-remodeled mitochondria for quality control.
    DOI:  https://doi.org/10.1083/jcb.202301091
  8. J Mol Cell Biol. 2023 Aug 17. pii: mjad051. [Epub ahead of print]
    Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells.
    Paweł Głodowicz, Konrad Kuczyński, Romain Val, André Dietrich, Katarzyna Rolle.
      Mutations in the small genome present in mitochondria often result in severe pathologies. Different genetic strategies have been explored, aiming to contribute to rescue such mutations. A number of these were based on the capacity of human mitochondria to import RNAs from the cytosol and were designed to repress the replication of the mutated genomes or to provide the organelles with wild-type versions of mutant transcripts. However, the mutant RNAs present in mitochondria turned out to be an obstacle to therapy and little attention has been devoted so far to their elimination. Here, we present the development of a strategy to knockdown mitochondrial RNAs in human cells using the transfer RNA-like structure of the Brome mosaic virus or the Tobacco mosaic virus as a shuttle to drive trans-cleaving ribozymes into the organelles in human cell lines. We obtained a specific knockdown of the targeted mitochondrial ATP6 mRNA, followed by a deep drop in ATP6 protein and a functional impairment of the oxidative phosphorylation chain. Our strategy opens a powerful approach to eliminate mutant organellar transcripts and to analyze the control and communication of the human organellar genetic system.
    Keywords:  RNA trafficking; human cells; mitochondria; ribozyme; tRNA-like structure; transcriptome manipulation
    DOI:  https://doi.org/10.1093/jmcb/mjad051
  9. Nucleic Acids Res. 2023 Aug 18. pii: gkad679. [Epub ahead of print]
    Structure-specific roles for PolG2-DNA complexes in maintenance and replication of mitochondrial DNA.
    Jessica L Wojtaszek, Kirsten E Hoff, Matthew J Longley, Parminder Kaur, Sara N Andres, Hong Wang, R Scott Williams, William C Copeland.
      The homodimeric PolG2 accessory subunit of the mitochondrial DNA polymerase gamma (Pol γ) enhances DNA binding and processive DNA synthesis by the PolG catalytic subunit. PolG2 also directly binds DNA, although the underlying molecular basis and functional significance are unknown. Here, data from Atomic Force Microscopy (AFM) and X-ray structures of PolG2-DNA complexes define dimeric and hexameric PolG2 DNA binding modes. Targeted disruption of PolG2 DNA-binding interfaces impairs processive DNA synthesis without diminishing Pol γ subunit affinities. In addition, a structure-specific DNA-binding role for PolG2 oligomers is supported by X-ray structures and AFM showing that oligomeric PolG2 localizes to DNA crossings and targets forked DNA structures resembling the mitochondrial D-loop. Overall, data indicate that PolG2 DNA binding has both PolG-dependent and -independent functions in mitochondrial DNA replication and maintenance, which provide new insight into molecular defects associated with PolG2 disruption in mitochondrial disease.
    DOI:  https://doi.org/10.1093/nar/gkad679
  10. EMBO J. 2023 Aug 14. e113481
    MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation.
    Yeon-Ji Park, Niranjan Dodantenna, Yonghyeon Kim, Tae-Hwan Kim, Ho-Soo Lee, Young-Suk Yoo, June Heo, Jae-Ho Lee, Myung-Hee Kwon, Ho Chul Kang, Jong-Soo Lee, Hyeseong Cho.
      The NLRP3 inflammasome plays a key role in responding to pathogens, and endogenous damage and mitochondria are intensively involved in inflammasome activation. The NLRP3 inflammasome forms multiprotein complexes and its sequential assembly is important for its activation. Here, we show that NLRP3 is ubiquitinated by the mitochondria-associated E3 ligase, MARCH5. Myeloid cell-specific March5 conditional knockout (March5 cKO) mice failed to secrete IL-1β and IL-18 and exhibited an attenuated mortality rate upon LPS or Pseudomonas aeruginosa challenge. Macrophages derived from March5 cKO mice also did not produce IL-1β and IL-18 after microbial infection. Mechanistically, MARCH5 interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination on K324 and K430 residues of NLRP3. Ubiquitination-defective NLRP3 mutants on K324 and K430 residues are not able to bind to NEK7, nor form NLRP3 oligomers leading to abortive ASC speck formation and diminished IL-1β production. Thus, MARCH5-dependent NLRP3 ubiquitination on the mitochondria is required for NLRP3-NEK7 complex formation and NLRP3 oligomerization. We propose that the E3 ligase MARCH5 is a regulator of NLRP3 inflammasome activation on the mitochondria.
    Keywords:  MARCH5; NEK7; NLRP3 inflammasome; mitochondria; ubiquitination
    DOI:  https://doi.org/10.15252/embj.2023113481
  11. Cell. 2023 Aug 17. pii: S0092-8674(23)00797-3. [Epub ahead of print]186(17): 3619-3631.e13
    A conserved family of immune effectors cleaves cellular ATP upon viral infection.
    Francois Rousset, Erez Yirmiya, Shahar Nesher, Alexander Brandis, Tevie Mehlman, Maxim Itkin, Sergey Malitsky, Adi Millman, Sarah Melamed, Rotem Sorek.
      During viral infection, cells can deploy immune strategies that deprive viruses of molecules essential for their replication. Here, we report a family of immune effectors in bacteria that, upon phage infection, degrade cellular adenosine triphosphate (ATP) and deoxyadenosine triphosphate (dATP) by cleaving the N-glycosidic bond between the adenine and sugar moieties. These ATP nucleosidase effectors are widely distributed within multiple bacterial defense systems, including cyclic oligonucleotide-based antiviral signaling systems (CBASS), prokaryotic argonautes, and nucleotide-binding leucine-rich repeat (NLR)-like proteins, and we show that ATP and dATP degradation during infection halts phage propagation. By analyzing homologs of the immune ATP nucleosidase domain, we discover and characterize Detocs, a family of bacterial defense systems with a two-component phosphotransfer-signaling architecture. The immune ATP nucleosidase domain is also encoded within diverse eukaryotic proteins with immune-like architectures, and we show biochemically that eukaryotic homologs preserve the ATP nucleosidase activity. Our findings suggest that ATP and dATP degradation is a cell-autonomous innate immune strategy conserved across the tree of life.
    Keywords:  ATP; CBASS; anti-phage; bacterial defense systems; innate immunity; phage; two-component system
    DOI:  https://doi.org/10.1016/j.cell.2023.07.020
  12. Nat Biotechnol. 2023 Aug 17.
    Machine learning predicts cellular response to genetic perturbation.
      
    DOI:  https://doi.org/10.1038/s41587-023-01907-4
  13. Nucleic Acids Res. 2023 Aug 17. pii: gkad659. [Epub ahead of print]
    Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels.
    Anka Güldenpfennig, Ann-Katrin Hopp, Lukas Muskalla, Patrick Manetsch, Fabio Raith, Lars Hellweg, Cyril Dördelmann, Deena M Leslie Pedrioli, Kai Johnsson, Giulio Superti-Furga, Michael O Hottiger.
      Though the effect of the recently identified mitochondrial NAD+ transporter SLC25A51 on glucose metabolism has been described, its contribution to other NAD+-dependent processes throughout the cell such as ADP-ribosylation remains elusive. Here, we report that absence of SLC25A51 leads to increased NAD+ concentration not only in the cytoplasm and but also in the nucleus. The increase is not associated with upregulation of the salvage pathway, implying an accumulation of constitutively synthesized NAD+ in the cytoplasm and nucleus. This results in an increase of PARP1-mediated nuclear ADP-ribosylation, as well as faster repair of DNA lesions induced by different single-strand DNA damaging agents. Lastly, absence of SLC25A51 reduces both MMS/Olaparib induced PARP1 chromatin retention and the sensitivity of different breast cancer cells to PARP1 inhibition. Together these results provide evidence that SLC25A51 might be a novel target to improve PARP1 inhibitor based therapies by changing subcellular NAD+ redistribution.
    DOI:  https://doi.org/10.1093/nar/gkad659
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