bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–11–13
twelve papers selected by
Marco Tigano, Thomas Jefferson University
  1. Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
  2. AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
  3. Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.
  4. PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.
  5. Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
  6. Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease.
  7. The phenotypic landscape of essential human genes.
  8. p53-mediated metabolic response to low doses of ionizing radiation.
  9. Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1.
  10. MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma.
  11. Mitochondrial Impairments in Peripheral Blood Mononuclear Cells of Multiple Sclerosis Patients.
  12. Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism.
  1. Nat Commun. 2022 Nov 07. 13(1): 6704
    Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
    Ayesha Sen, Sebastian Kallabis, Felix Gaedke, Christian Jüngst, Julia Boix, Julian Nüchel, Kanjanamas Maliphol, Julia Hofmann, Astrid C Schauss, Marcus Krüger, Rudolf J Wiesner, David Pla-Martín.
      Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.
    DOI:  https://doi.org/10.1038/s41467-022-34205-9
  2. Sci Adv. 2022 Nov 11. 8(45): eabo7956
    AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
    Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.
      Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abo7956
  3. J Exp Med. 2023 Jan 02. pii: e20220829. [Epub ahead of print]220(1):
    Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.
    Tina Schumann, Santiago Costas Ramon, Nadja Schubert, Mohamad Aref Mayo, Melanie Hega, Katharina Isabell Maser, Servi-Remzi Ada, Lukas Sydow, Mona Hajikazemi, Markus Badstübner, Patrick Müller, Yan Ge, Farhad Shakeri, Andreas Buness, Benjamin Rupf, Stefan Lienenklaus, Barbara Utess, Lina Muhandes, Michael Haase, Luise Rupp, Marc Schmitz, Thomas Gramberg, Nicolas Manel, Gunther Hartmann, Thomas Zillinger, Hiroki Kato, Stefan Bauer, Alexander Gerbaulet, Katrin Paeschke, Axel Roers, Rayk Behrendt.
      Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.
    DOI:  https://doi.org/10.1084/jem.20220829
  4. Cancer Treat Res Commun. 2022 Sep 27. pii: S2468-2942(22)00135-6. [Epub ahead of print]33 100644
    PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.
    Karina Galoian, Victoria Dahl, Andres Perez, Carina Denny, Beatrice Becker, Anil Sedani, Alexandra Moran, Daniel Martinez, Aaron Hoyt, Jeffrey Brown.
       BACKGROUND: Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells.
    MATERIALS AND METHODS: Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1).
    RESULTS: The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels.
    CONCLUSION: PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.
    Keywords:  Cellular stress; Chondrosarcoma; Proline-rich polypeptide (PRP-1); Toll-like receptors; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100644
  5. Nat Commun. 2022 Nov 09. 13(1): 6779
    Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
    Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I Yule, György Hajnóczky.
      Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when 'parked', mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.
    DOI:  https://doi.org/10.1038/s41467-022-34365-8
  6. Nucleic Acids Res. 2022 Nov 09. pii: gkac1028. [Epub ahead of print]
    Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease.
    Tingting Yu, Yi Zhang, Wen-Qiang Zheng, Siqi Wu, Guoqiang Li, Yong Zhang, Niu Li, Ruen Yao, Pengfei Fang, Jian Wang, Xiao-Long Zhou.
      Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654-14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases.
    DOI:  https://doi.org/10.1093/nar/gkac1028
  7. Cell. 2022 Nov 02. pii: S0092-8674(22)01359-9. [Epub ahead of print]
    The phenotypic landscape of essential human genes.
    Luke Funk, Kuan-Chung Su, Jimmy Ly, David Feldman, Avtar Singh, Brittania Moodie, Paul C Blainey, Iain M Cheeseman.
      Understanding the basis for cellular growth, proliferation, and function requires determining the roles of essential genes in diverse cellular processes, including visualizing their contributions to cellular organization and morphology. Here, we combined pooled CRISPR-Cas9-based functional screening of 5,072 fitness-conferring genes in human HeLa cells with microscopy-based imaging of DNA, the DNA damage response, actin, and microtubules. Analysis of >31 million individual cells identified measurable phenotypes for >90% of gene knockouts, implicating gene targets in specific cellular processes. Clustering of phenotypic similarities based on hundreds of quantitative parameters further revealed co-functional genes across diverse cellular activities, providing predictions for gene functions and associations. By conducting pooled live-cell screening of ∼450,000 cell division events for 239 genes, we additionally identified diverse genes with functional contributions to chromosome segregation. Our work establishes a resource detailing the consequences of disrupting core cellular processes that represents the functional landscape of essential human genes.
    Keywords:  CRISPR-Cas9; cell division; essential genes; functional genomics; high-content screening; in situ sequencing; microscopy; mitosis; morphology; optical pooled screening
    DOI:  https://doi.org/10.1016/j.cell.2022.10.017
  8. Int J Radiat Biol. 2022 Nov 10. 1-20
    p53-mediated metabolic response to low doses of ionizing radiation.
    Isha Nagpal, Zhi-Min Yuan.
       PURPOSE: Unlike treatment with high doses of radiation that causes considerable DNA damage resulting in injury and p53 activation, exposure of cells or whole animals to low doses of radiation (LDR, ∼10cGy) can induce a protective radioadaptive response. Despite ample information about the contribution of the p53 pathway to high doses of radiation-induced effects, our understanding of the role of p53 in LDR-induced response remains incomplete. This review provides a brief summary of the p53 response to LDR exposure focusing on metabolic regulation.
    CONCLUSION: Consistent with growing evidence indicating a critical role of metabolic pathways in the modulation of stress responses, the radioadaptive response was mediated by the LDR-induced metabolic switch from oxidative phosphorylation to glycolysis. Remarkably, this metabolic reprogramming depends on p53 downregulation, suggesting a previously unrecognized p53-mediated metabolic response. Of note is that the LDR-induced p53 response is temporary but may become persistent if LDR exposure is recurrent and protracted. While further investigation is necessary, the model where LDR induces p53 downregulation concurrent with anabolic reprogramming may offer novel mechanistic insight into the radioadaptive response. It suggests a model in which LDR exposure is protective when transient or intermittent but may become detrimental when chronic because prolonged p53 downregulation would lead to inactivation of this critical tumor suppressor, causing a loss of p53-dependent DNA damage checkpoint, genomic instability, dysregulated metabolism, and thus increased cancer risk.
    Keywords:  DNA damage; Genomic instability; Low Dose Radiation; Oxidative phosphorylation; P53 down-regulation; Radioadaptive response
    DOI:  https://doi.org/10.1080/09553002.2022.2142983
  9. Oncogene. 2022 Nov 10.
    Nuclear FGFR1 promotes pancreatic stellate cell-driven invasion through up-regulation of Neuregulin 1.
    Abigail S Coetzee, Edward P Carter, Lucía Rodríguez-Fernández, James Heward, Qiaoying Wang, Saadia A Karim, Lina Boughetane, Christopher Milton, Firat Uyulur, Jennifer P Morton, Hemant M Kocher, Richard P Grose.
      Pancreatic stellate cells (PSCs) are key to the treatment-refractory desmoplastic phenotype of pancreatic ductal adenocarcinoma (PDAC) and have received considerable attention as a stromal target for cancer therapy. This approach demands detailed understanding of their pro- and anti-tumourigenic effects. Interrogating PSC-cancer cell interactions in 3D models, we identified nuclear FGFR1 as critical for PSC-led invasion of cancer cells. ChIP-seq analysis of FGFR1 in PSCs revealed a number of FGFR1 interaction sites within the genome, notably NRG1, which encodes the ERBB ligand Neuregulin. We show that nuclear FGFR1 regulates transcription of NRG1, which in turn acts in autocrine fashion through an ERBB2/4 heterodimer to promote invasion. In support of this, recombinant NRG1 in 3D model systems rescued the loss of invasion incurred by FGFR inhibition. In vivo we demonstrate that, while FGFR inhibition does not affect the growth of pancreatic tumours in mice, local invasion into the pancreas is reduced. Thus, FGFR and NRG1 may present new stromal targets for PDAC therapy.
    DOI:  https://doi.org/10.1038/s41388-022-02513-5
  10. Front Oncol. 2022 ;12 1000677
    MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma.
    Arianna Romani, Enrico Zauli, Giorgio Zauli, Saleh AlMesfer, Samar Al-Swailem, Rebecca Voltan.
      MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.
    Keywords:  MDM2 inhibitors; Nutlin-3; mitochondrial metabolism; p53; retina; retinoblastoma
    DOI:  https://doi.org/10.3389/fonc.2022.1000677
  11. Biology (Basel). 2022 Nov 08. pii: 1633. [Epub ahead of print]11(11):
    Mitochondrial Impairments in Peripheral Blood Mononuclear Cells of Multiple Sclerosis Patients.
    María Inmaculada Domínguez-Mozo, María Celeste García-Frontini Nieto, María Isabel Gómez-Calcerrada, Silvia Pérez-Pérez, María Ángel García-Martínez, Luisa María Villar, Noelia Villarrubia, Lucienne Costa-Frossard, Rafael Arroyo, Roberto Alvarez-Lafuente.
      Although impaired mitochondrial function has been proposed as a hallmark of multiple sclerosis (MS) disease, few studies focus on the mitochondria of immune cells. We aimed to compare the mitochondrial function of the peripheral blood mononuclear cells (PBMCs) from MS patients with (M+) and without (M-) lipid-specific oligoclonal immunoglobulin M bands (LS-OCMB), and healthydonors (HD). We conducted an exploratory cross-sectional study with 19 untreated MS patients (M+ = 9 and M- = 10) and 17 HDs. Mitochondrial superoxide anion production and mitochondrial mass in PBMCs were assessed without and with phytohemagglutinin by flow cytometry. The PBMCs' mitochondrial function was analyzed using Seahorse technology. Superoxide anion production corrected by the mitochondrial mass was higher in MS patients compared with HDs (p = 0.011). Mitochondrial function from M+ patients showed some impairments compared with M- patients. Without stimulus, we observed higher proton leak (p = 0.041) but lower coupling efficiency (p = 0.041) in M+ patients; and under stimulation, lower metabolic potential ECAR (p = 0.011), and lower stressed OCR/ECAR in the same patients. Exclusively among M+ patients, we described a higher mitochondrial dysfunction in the oldest ones. The mitochondrial impairments found in the PBMCs from MS patients, specifically in M+ patients, could help to better understand the disease's physiopathology.
    Keywords:  lipid-specific oligoclonal immunoglobulin M bands (LS-OCMB); mitochondria; multiple sclerosis
    DOI:  https://doi.org/10.3390/biology11111633
  12. Antioxidants (Basel). 2022 Nov 07. pii: 2202. [Epub ahead of print]11(11):
    Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism.
    Chenbin Bian, Zhuangzhuang Zheng, Jing Su, Huanhuan Wang, Sitong Chang, Ying Xin, Xin Jiang.
      Radiotherapy failure and poor tumor prognosis are primarily attributed to radioresistance. Improving the curative effect of radiotherapy and delaying cancer progression have become difficult problems for clinicians. Glucose metabolism has long been regarded as the main metabolic process by which tumor cells meet their bioenergetic and anabolic needs, with the complex interactions between the mitochondria and tumors being ignored. This misconception was not dispelled until the early 2000s; however, the cellular molecules and signaling pathways involved in radioresistance remain incompletely defined. In addition to being a key metabolic site that regulates tumorigenesis, mitochondria can influence the radiation effects of malignancies by controlling redox reactions, participating in oxidative phosphorylation, producing oncometabolites, and triggering apoptosis. Therefore, the mitochondria are promising targets for the development of novel anticancer drugs. In this review, we summarize the internal relationship and related mechanisms between mitochondrial metabolism and cancer radioresistance, thus exploring the possibility of targeting mitochondrial signaling pathways to reverse radiation insensitivity. We suggest that attention should be paid to the potential value of mitochondria in prolonging the survival of cancer patients.
    Keywords:  apoptosis; oncometabolites; oxidative phosphorylation; radioresistance; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11112202
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:25.