bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–07–07
twelve papers selected by
Marco Tigano, Thomas Jefferson University
  1. The germline coordinates mitokine signaling.
  2. A mitochondrial checkpoint to NF-κB signaling.
  3. GTPBP8 plays a role in mitoribosome formation in human mitochondria.
  4. Bridging lipid metabolism and mitochondrial genome maintenance.
  5. Mitochondrial genetics through the lens of single-cell multi-omics.
  6. Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
  7. Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
  8. Functional multi-organelle units control inflammatory lipid metabolism of macrophages.
  9. Compositionally unique mitochondria in filopodia support cellular migration.
  10. LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.
  11. Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence.
  12. Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.
  1. Cell. 2024 Jun 26. pii: S0092-8674(24)00650-0. [Epub ahead of print]
    The germline coordinates mitokine signaling.
    Koning Shen, Jenni Durieux, Cesar G Mena, Brant M Webster, C Kimberly Tsui, Hanlin Zhang, Larry Joe, Kristen M Berendzen, Andrew Dillin.
      The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.
    Keywords:  C. elegans; aging; germline; lipids; mitochondria; mtUPR; proteostasis; stress response
    DOI:  https://doi.org/10.1016/j.cell.2024.06.010
  2. Cell Death Dis. 2024 Jul 03. 15(7): 477
    A mitochondrial checkpoint to NF-κB signaling.
    Emma Guilbaud, Lorenzo Galluzzi.
      Mitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization.
    DOI:  https://doi.org/10.1038/s41419-024-06868-3
  3. Nat Commun. 2024 Jul 05. 15(1): 5664
    GTPBP8 plays a role in mitoribosome formation in human mitochondria.
    Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.
      Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.
    DOI:  https://doi.org/10.1038/s41467-024-50011-x
  4. J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)01999-9. [Epub ahead of print] 107498
    Bridging lipid metabolism and mitochondrial genome maintenance.
    Casadora Boone, Samantha C Lewis.
      Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.
    Keywords:  Mitochondria; lipid metabolism; lipotoxicity; mitochondrial DNA (mtDNA); mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107498
  5. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  6. Life Sci Alliance. 2024 Sep;pii: e202302396. [Epub ahead of print]7(9):
    Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
    Matthew R Krieger, Melania Abrahamian, Kevin L He, Sean Atamdede, Hesamedin Hakimjavadi, Milica Momcilovic, Dejerianne Ostrow, Simran Ds Maggo, Yik Pui Tsang, Xiaowu Gai, Guillaume F Chanfreau, David B Shackelford, Michael A Teitell, Carla M Koehler.
      In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
    DOI:  https://doi.org/10.26508/lsa.202302396
  7. Aging Cell. 2024 Jul 02. e14262
    Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
    Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.
      The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
    Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1111/acel.14262
  8. Nat Cell Biol. 2024 Jul 05.
    Functional multi-organelle units control inflammatory lipid metabolism of macrophages.
    Julia A Zimmermann, Kerstin Lucht, Manuel Stecher, Chahat Badhan, Katharina M Glaser, Maximilian W Epple, Lena R Koch, Ward Deboutte, Thomas Manke, Klaus Ebnet, Frauke Brinkmann, Olesja Fehler, Thomas Vogl, Ev-Marie Schuster, Anna Bremser, Joerg M Buescher, Angelika S Rambold.
      Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.
    DOI:  https://doi.org/10.1038/s41556-024-01457-0
  9. bioRxiv. 2024 Jun 21. pii: 2024.06.21.600105. [Epub ahead of print]
    Compositionally unique mitochondria in filopodia support cellular migration.
    Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.
      Local metabolic demand within cells varies widely and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of MICOS, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery that we term METEORs. METEORs have a unique composition; MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.
    DOI:  https://doi.org/10.1101/2024.06.21.600105
  10. EMBO J. 2024 Jul 01.
    LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.
    Arianna Mangiavacchi, Gabriele Morelli, Sjur Reppe, Alfonso Saera-Vila, Peng Liu, Benjamin Eggerschwiler, Huoming Zhang, Dalila Bensaddek, Elisa A Casanova, Carolina Medina Gomez, Vid Prijatelj, Francesco Della Valle, Nazerke Atinbayeva, Juan Carlos Izpisua Belmonte, Fernando Rivadeneira, Paolo Cinelli, Kaare Morten Gautvik, Valerio Orlando.
      Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.
    Keywords:  Inflammation; Osteoblast; PKR; Transposable Elements; dsRNA
    DOI:  https://doi.org/10.1038/s44318-024-00143-z
  11. Aging Cell. 2024 Jul 02. e14265
    Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence.
    Kangkang Yu, Feifei Li, Ling Ye, Fanyuan Yu.
      Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence-associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G-quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence-associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence.
    Keywords:  G‐quadruplex; biomarker; mesenchymal stem cell; mitochondrial genome; senescence
    DOI:  https://doi.org/10.1111/acel.14265
  12. Cell Stem Cell. 2024 Jun 25. pii: S1934-5909(24)00215-7. [Epub ahead of print]
    Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening.
    Chengfang Zhou, Mei Kuang, Yin Tao, Jianming Wang, Yu Luo, Yinghao Fu, Zhe Chen, Yuanyuan Liu, Zhigang Li, Weiru Wu, Li Wang, Ying Dou, Junping Wang, Yu Hou.
      Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrin diminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrin overexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppif haploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.
    Keywords:  Nynrin; Ppif; ROS; hematopoietic stem cells; irradiation; mPTP opening; mitochondrial membrane potential; mitochondrial metabolism; mitochondrial swelling; radiotherapy
    DOI:  https://doi.org/10.1016/j.stem.2024.06.007
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