bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024‒06‒16
fifteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
  2. Unique architectural features of mammalian mitochondrial protein synthesis.
  3. Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
  4. The rate and nature of mitochondrial DNA mutations in human pedigrees.
  5. Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease.
  6. Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
  7. Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
  8. Annexin A1 protects epidermal stem cells against ultraviolet-B irradiation-induced mitochondrial dysfunction.
  9. Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.
  10. Release of CD36-associated cell-free mitochondrial DNA and RNA as a hallmark of space environment response.
  11. A Fully-Automated Senescence Test (FAST) for the high-throughput quantification of senescence-associated markers.
  12. Metabolic inflexibility promotes mitochondrial health during liver regeneration.
  13. TUFM in health and disease: exploring its multifaceted roles.
  14. IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome.
  15. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
  1. Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]
    MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
    Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.
      Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
    Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2024.05.017
  2. Trends Cell Biol. 2024 Jun 08. pii: S0962-8924(24)00097-7. [Epub ahead of print]
    Unique architectural features of mammalian mitochondrial protein synthesis.
    Oliver Rackham, Martin Saurer, Nenad Ban, Aleksandra Filipovska.
      Mitochondria rely on coordinated expression of their own mitochondrial DNA (mtDNA) with that of the nuclear genome for their biogenesis. The bacterial ancestry of mitochondria has given rise to unique and idiosyncratic features of the mtDNA and its expression machinery that can be specific to different organisms. In animals, the mitochondrial protein synthesis machinery has acquired many new components and mechanisms over evolution. These include several new ribosomal proteins, new stop codons and ways to recognise them, and new mechanisms to deliver nascent proteins into the mitochondrial inner membrane. Here we describe the mitochondrial protein synthesis machinery in mammals and its unique mechanisms of action elucidated to date and highlight the technologies poised to reveal the next generation of discoveries in mitochondrial translation.
    Keywords:  RNA; mitochondria; mitochondrial disease; ribosomes; translation
    DOI:  https://doi.org/10.1016/j.tcb.2024.05.001
  3. Sci Rep. 2024 Jun 14. 14(1): 13789
    Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues.
    Alexander Bury, Angela Pyle, Amy E Vincent, Paolo Actis, Gavin Hudson.
      Mitochondrial function is critical to continued cellular vitality and is an important contributor to a growing number of human diseases. Mitochondrial dysfunction is typically heterogeneous, mediated through the clonal expansion of mitochondrial DNA (mtDNA) variants in a subset of cells in a given tissue. To date, our understanding of the dynamics of clonal expansion of mtDNA variants has been technically limited to the single cell-level. Here, we report the use of nanobiopsy for subcellular sampling from human tissues, combined with next-generation sequencing to assess subcellular mtDNA mutation load in human tissue from mitochondrial disease patients. The ability to map mitochondrial mutation loads within individual cells of diseased tissue samples will further our understanding of mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41598-024-64455-0
  4. Cell. 2024 Jun 03. pii: S0092-8674(24)00531-2. [Epub ahead of print]
    The rate and nature of mitochondrial DNA mutations in human pedigrees.
    Erla R Árnadóttir, Kristján H S Moore, Valdís B Guðmundsdóttir, S Sunna Ebenesersdóttir, Kamran Guity, Hákon Jónsson, Kári Stefánsson, Agnar Helgason.
      We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
    Keywords:  germline bottleneck; germline selection; hypermutability; mitochondria; mitochondrial bottleneck; mtDNA; mutation rate; negative selection; pathogenic mutations; pedigrees
    DOI:  https://doi.org/10.1016/j.cell.2024.05.022
  5. Cell Commun Signal. 2024 Jun 13. 22(1): 328
    Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease.
    Ke Wei, Tao Chen, Hao Fang, Xianjuan Shen, Zhiyuan Tang, Jianmei Zhao.
      BACKGROUND: Kawasaki disease (KD) is an immune vasculitis of unknown origin, characterized by transient inflammation. The activation of the cGAS-STING pathway, triggered by mitochondrial DNA (mtDNA) release, has been implicated in the onset of KD. However, its specific role in the progression of inflammation during KD's acute phase remains unclear.METHODS: We measured mtDNA and 2'3'-cGAMP expression in KD patient serum using RT-qPCR and ELISA. A murine model of KD was induced by injecting Lactobacillus casei cell wall extract (LCWE), after which cGAS-STING pathway activation and inflammatory markers were assessed via immunohistochemistry, western blot, and RT-qPCR. Human umbilical vein endothelial cells (HUVECs) were treated with KD serum and modulators of the cGAS-STING pathway for comparative analysis. Mitochondrial function was evaluated using Mitosox staining, mPTP opening was quantified by fluorescence microscopy, and mitochondrial membrane potential (MMP) was determined with JC-1 staining.
    RESULTS: KD patient serum exhibited increased mtDNA and 2'3'-cGAMP expression, with elevated levels of pathway-related proteins and inflammatory markers observed in both in vivo and in vitro models. TEM confirmed mitochondrial damage, and further studies demonstrated that inhibition of mPTP opening reduced mtDNA release, abrogated cGAS-STING pathway activation, and mitigated inflammation.
    CONCLUSION: These findings indicate that mtDNA released through the mPTP is a critical activator of the cGAS-STING pathway, contributing significantly to KD-associated inflammation. Targeting mtDNA release or the cGAS-STING pathway may offer novel therapeutic approaches for KD management.
    Keywords:  Kawasaki disease; cGAS-STING pathway; mPTP; mtDNA
    DOI:  https://doi.org/10.1186/s12964-024-01677-9
  6. Cell Death Dis. 2024 Jun 10. 15(6): 405
    Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease.
    Patricia Morcillo, Khushbu Kabra, Kevin Velasco, Hector Cordero, Sarah Jennings, Taekyung D Yun, Delfina Larrea, H Orhan Akman, Eric A Schon.
      Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM "signature". We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a "MAM-OxPhos" axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.
    DOI:  https://doi.org/10.1038/s41419-024-06781-9
  7. Cell Metab. 2024 Jun 07. pii: S1550-4131(24)00190-6. [Epub ahead of print]
    Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
    Zheng Wu, Divya Bezwada, Feng Cai, Robert C Harris, Bookyung Ko, Varun Sondhi, Chunxiao Pan, Hieu S Vu, Phong T Nguyen, Brandon Faubert, Ling Cai, Hongli Chen, Misty Martin-Sandoval, Duyen Do, Wen Gu, Yuanyuan Zhang, Yuannyu Zhang, Bailey Brooks, Sherwin Kelekar, Lauren G Zacharias, K Celeste Oaxaca, Joao S Patricio, Thomas P Mathews, Javier Garcia-Bermudez, Min Ni, Ralph J DeBerardinis.
      Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
    Keywords:  HPRT1; NAD(+):NADH ratio; electron transport chain; metabolomics; purine metabolism; stable isotopes
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.014
  8. Arch Dermatol Res. 2024 Jun 14. 316(7): 385
    Annexin A1 protects epidermal stem cells against ultraviolet-B irradiation-induced mitochondrial dysfunction.
    Lingzhi Ge, Wenfang Chen, Fangli Wei.
      Ultraviolet-B (UV-B) radiation overexposure causes function impairment of epidermal stem cells (ESCs). We explored the mechanism of Annexin A1 (ANXA1) ameliorating UV-B-induced ESC mitochondrial dysfunction/cell injury. ESCs were cultured in vitro and irradiated with different doses of UV-B. Cell viability/ANXA1 protein level were assessed. After oe-ANXA1 transfection, ESCs were treated with oe-ANXA1/UV-B irradiation/CCCP/CCG-1423/3-methyladenine for 12 h. Cell viability/death, and adenosine triphosphate (ATP)/reactive oxygen species (ROS) levels were determined. Mitochondrial membrane potential (MMP) changes/DNA (mtDNA) content/oxygen consumption and RhoA activation were assessed. ROCK1/p-MYPT1/MYPT1/(LC3BII/I)/Beclin-1/p62 protein levels were determined. Mitochondrial morphology was observed. Mito-Tracker Green (MTG) and LC3B levels were determined. UV-B irradiation decreased cell viability/ANXA1 expression in a dose-dependent manner. UV-B-treated ESCs exhibited reduced cell viability/ATP content/MMP level/mitochondrial respiratory control ratio/mtDNA number/RhoA activity/MYPT1 phosphorylation/MTG+LC3B+ cells/(LC3BII/I) and Beclin-1 proteins, increased cell death/ROS/p62/IL-1β/IL-6/TNF-α expression, contracted mitochondrial, disappeared mitochondrial cristae, and increased vacuolar mitochondria, which were averted by ANXA1 overexpression, suggesting that UV-B induced ESC mitochondrial dysfunction/cell injury/inflammation by repressing mitophagy, but ANXA1 promoted mitophagy by activating the RhoA/ROCK1 pathway, thus repressing UV-B's effects. Mitophagy activation ameliorated UV-B-caused ESC mitochondrial dysfunction/cell injury/inflammation. Mitophagy inhibition partly diminished ANXA1-ameliorated UV-B's effects. Conjointly, ANXA1 promoted mitophagy by activating the RhoA/ROCK1 pathway, thereby improving UV-B-induced ESC mitochondrial dysfunction/cell injury.
    Keywords:  Annexin A1; Epidermal stem cells; Mitochondrial dysfunction; ROCK1; RhoA; Ultraviolet B
    DOI:  https://doi.org/10.1007/s00403-024-02875-8
  9. bioRxiv. 2024 May 30. pii: 2024.05.29.596517. [Epub ahead of print]
    Heterogeneous brain region-specific responses to astrocytic mitochondrial DNA damage in mice.
    Daniela A Ayala, Anthony Matarazzo, Bonnie L Seaberg, Misha Patel, Eliana Tijerina, Camryn Matthews, Gabriel Bizi, Ashton Brown, Alan Ta, Mendell Rimer, Rahul Srinivasan.
      Astrocytes use Ca 2+ signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and in their response to noxious stimuli between brain regions. Indeed, astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on their ATP generation and Ca 2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca 2+ signaling in astrocytes, the extent of this regulation into the rich diversity of astrocytes in different brain regions remains largely unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for proper astrocyte function, however, few insights into possible diverse responses to this noxious stimulus from astrocytes in different brain areas were reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI, which expresses the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two distinct brain regions, the dorsolateral striatum, and the hippocampal dentate gyrus, and we show that Mito-PstI can induce astrocytic mtDNA loss in vivo , but with remarkable brain-region-dependent differences on mitochondrial dynamics, spontaneous Ca 2+ fluxes and astrocytic as well as microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca 2+ signaling in a brain-region-selective manner.
    DOI:  https://doi.org/10.1101/2024.05.29.596517
  10. Nat Commun. 2024 Jun 11. 15(1): 4814
    Release of CD36-associated cell-free mitochondrial DNA and RNA as a hallmark of space environment response.
    Nailil Husna, Tatsuya Aiba, Shin-Ichiro Fujita, Yoshika Saito, Dai Shiba, Takashi Kudo, Satoru Takahashi, Satoshi Furukawa, Masafumi Muratani.
      A detailed understanding of how spaceflight affects human health is essential for long-term space exploration. Liquid biopsies allow for minimally-invasive multi-omics assessments that can resolve the molecular heterogeneity of internal tissues. Here, we report initial results from the JAXA Cell-Free Epigenome Study, a liquid biopsy study with six astronauts who resided on the International Space Station (ISS) for more than 120 days. Analysis of plasma cell-free RNA (cfRNA) collected before, during, and after spaceflight confirms previously reported mitochondrial dysregulation in space. Screening with 361 cell surface marker antibodies identifies a mitochondrial DNA-enriched fraction associated with the scavenger receptor CD36. RNA-sequencing of the CD36 fraction reveals tissue-enriched RNA species, suggesting the plasma mitochondrial components originated from various tissues. We compare our plasma cfRNA data to mouse plasma cfRNA data from a previous JAXA mission, which had used on-board artificial gravity, and discover a link between microgravity and the observed mitochondrial responses.
    DOI:  https://doi.org/10.1038/s41467-023-41995-z
  11. Geroscience. 2024 Jun 13.
    A Fully-Automated Senescence Test (FAST) for the high-throughput quantification of senescence-associated markers.
    Francesco Neri, Selma N Takajjart, Chad A Lerner, Pierre-Yves Desprez, Birgit Schilling, Judith Campisi, Akos A Gerencser.
      Cellular senescence is a major driver of aging and age-related diseases. Quantification of senescent cells remains challenging due to the lack of senescence-specific markers and generalist, unbiased methodology. Here, we describe the Fully-Automated Senescence Test (FAST), an image-based method for the high-throughput, single-cell assessment of senescence in cultured cells. FAST quantifies three of the most widely adopted senescence-associated markers for each cell imaged: senescence-associated β-galactosidase activity (SA-β-Gal) using X-Gal, proliferation arrest via lack of 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and enlarged morphology via increased nuclear area. The presented workflow entails microplate image acquisition, image processing, data analysis, and graphing. Standardization was achieved by (i) quantifying colorimetric SA-β-Gal via optical density; (ii) implementing staining background controls; and (iii) automating image acquisition, image processing, and data analysis. In addition to the automated threshold-based scoring, a multivariate machine learning approach is provided. We show that FAST accurately quantifies senescence burden and is agnostic to cell type and microscope setup. Moreover, it effectively mitigates false-positive senescence marker staining, a common issue arising from culturing conditions. Using FAST, we compared X-Gal with fluorescent C12FDG live-cell SA-β-Gal staining on the single-cell level. We observed only a modest correlation between the two, indicating that those stains are not trivially interchangeable. Finally, we provide proof of concept that our method is suitable for screening compounds that modify senescence burden. This method will be broadly useful to the aging field by enabling rapid, unbiased, and user-friendly quantification of senescence burden in culture, as well as facilitating large-scale experiments that were previously impractical.
    Keywords:  Aging; Cellular senescence; High-content image analysis; High-throughput screening; Machine learning; Senescence-associated-β-galactosidase
    DOI:  https://doi.org/10.1007/s11357-024-01167-3
  12. Science. 2024 Jun 14. 384(6701): eadj4301
    Metabolic inflexibility promotes mitochondrial health during liver regeneration.
    Xun Wang, Cameron J Menezes, Yuemeng Jia, Yi Xiao, Siva Sai Krishna Venigalla, Feng Cai, Meng-Hsiung Hsieh, Wen Gu, Liming Du, Jessica Sudderth, Dohun Kim, Spencer D Shelton, Claire B Llamas, Yu-Hsuan Lin, Min Zhu, Salma Merchant, Divya Bezwada, Sherwin Kelekar, Lauren G Zacharias, Thomas P Mathews, Gerta Hoxhaj, R Max Wynn, Uttam K Tambar, Ralph J DeBerardinis, Hao Zhu, Prashant Mishra.
      Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial β-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.
    DOI:  https://doi.org/10.1126/science.adj4301
  13. Front Immunol. 2024 ;15 1424385
    TUFM in health and disease: exploring its multifaceted roles.
    Ning Liu, Bo Pang, Longfei Kang, Dongyun Li, Xia Jiang, Chuan-Min Zhou.
      The nuclear-encoded mitochondrial protein Tu translation elongation factor, mitochondrial (TUFM) is well-known for its role in mitochondrial protein translation. Originally discovered in yeast, TUFM demonstrates significant evolutionary conservation from prokaryotes to eukaryotes. Dysregulation of TUFM has been associated with mitochondrial disorders. Although early hypothesis suggests that TUFM is localized within mitochondria, recent studies identify its presence in the cytoplasm, with this subcellular distribution being linked to distinct functions of TUFM. Significantly, in addition to its established function in mitochondrial protein quality control, recent research indicates a broader involvement of TUFM in the regulation of programmed cell death processes (e.g., autophagy, apoptosis, necroptosis, and pyroptosis) and its diverse roles in viral infection, cancer, and other disease conditions. This review seeks to offer a current summary of TUFM's biological functions and its complex regulatory mechanisms in human health and disease. Insight into these intricate pathways controlled by TUFM may lead to the potential development of targeted therapies for a range of human diseases.
    Keywords:  TUFM; autophagy; cancer; mitochondria; virus
    DOI:  https://doi.org/10.3389/fimmu.2024.1424385
  14. Transl Oncol. 2024 Jun 12. pii: S1936-5233(24)00157-8. [Epub ahead of print]46 102030
    IL-6 knockdown in a model of the human bone marrow, abrogates DNA damage induction in bystander cells post-chemotherapy induced cytokine release syndrome.
    Harshini S H Asurappulige, Michael R Ladomery, H Ruth Morse.
      Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT). Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls. Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.
    Keywords:  Bone marrow; Bystander effect; Cytokine release syndrome; Cytokine storm; Genetic toxicology
    DOI:  https://doi.org/10.1016/j.tranon.2024.102030
  15. Front Cell Dev Biol. 2024 ;12 1410245
    Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    Álvaro Antolínez-Fernández, Paula Esteban-Ramos, Miguel Ángel Fernández-Moreno, Paula Clemente.
      Mitochondria play a central role in cellular metabolism producing the necessary ATP through oxidative phosphorylation. As a remnant of their prokaryotic past, mitochondria contain their own genome, which encodes 13 subunits of the oxidative phosphorylation system, as well as the tRNAs and rRNAs necessary for their translation in the organelle. Mitochondrial protein synthesis depends on the import of a vast array of nuclear-encoded proteins including the mitochondrial ribosome protein components, translation factors, aminoacyl-tRNA synthetases or assembly factors among others. Cryo-EM studies have improved our understanding of the composition of the mitochondrial ribosome and the factors required for mitochondrial protein synthesis and the advances in next-generation sequencing techniques have allowed for the identification of a growing number of genes involved in mitochondrial pathologies with a defective translation. These disorders are often multisystemic, affecting those tissues with a higher energy demand, and often present with neurodegenerative phenotypes. In this article, we review the known proteins required for mitochondrial translation, the disorders that derive from a defective mitochondrial protein synthesis and the animal models that have been established for their study.
    Keywords:  OxPhos; mitochondria; mitochondrial disorders; mitoribosome; translation
    DOI:  https://doi.org/10.3389/fcell.2024.1410245
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