bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒12‒24
nineteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
  2. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
  3. Gene dosage adaptations to mtDNA depletion and mitochondrial protein stress in budding yeast.
  4. Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.
  5. Muscle immune cells protect mitochondrial organelles during exercise.
  6. Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network.
  7. DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
  8. Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.
  9. The competitive landscape of the dsRNA world.
  10. Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation.
  11. Spontaneous Mutations in Saccharomyces cerevisiae mtDNA Increase Cell-to-Cell Variation in mtDNA Amount.
  12. Single-Cell Radiation Response Scoring with the Deep Learning Algorithm CeCILE 2.0.
  13. Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.
  14. Nuclear RPSA senses viral nucleic acids to promote the innate inflammatory response.
  15. Regulation of Mitochondrial Metabolism by Hepatitis B Virus.
  16. Mitochondrial replication's role in vertebrate mtDNA strand asymmetry.
  17. Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology.
  18. Irradiation Induces Gasdermin E-Triggered Tumor Immunity to Inhibit Esophageal Carcinoma Cell Survival.
  19. A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.
  1. Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]
    FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
    Kun Gao, Xiayun Xu, Chenji Wang.
      Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.
    Keywords:  BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1016/j.molmed.2023.11.017
  2. Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):
    Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
    Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.
      Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.
    Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response
    DOI:  https://doi.org/10.3390/ijms242417423
  3. G3 (Bethesda). 2023 Dec 21. pii: jkad272. [Epub ahead of print]
    Gene dosage adaptations to mtDNA depletion and mitochondrial protein stress in budding yeast.
    Joshua T McNamara, Jin Zhu, Yuhao Wang, Rong Li.
      Mitochondria contain a local genome (mtDNA) comprising a small number of genes necessary for respiration, mitochondrial transcription and translation, and other vital functions. Various stressors can destabilize mtDNA leading to mtDNA loss. While some cells can survive mtDNA loss, they exhibit various deficiencies. Here, we investigated the impact of proteotoxicity on mitochondrial function by inducing mitochondrial unfolded protein stress in budding yeast. This led to rapid mtDNA loss, but aerobic conditioning imparted transient resistance to mitochondrial protein stress. We present a quantitative model of mtDNA loss in a growing cell population and measure its parameters. To identify genetic adaptations to mtDNA depletion, we performed a genome-wide screen for gene dosage increases that affect the growth of cells lacking mtDNA. The screen revealed a set of dosage suppressors that alleviate the growth impairment in mtDNA-deficient cells. Additionally, we show that these suppressors of mtDNA stress both bolster cell proliferation and prevent mtDNA loss during mitochondrial protein stress.
    Keywords:  copy number variation; functional genomics; mitochondria; mtDNA; protein aggregates; proteostasis; respiration; stress resistance
    DOI:  https://doi.org/10.1093/g3journal/jkad272
  4. Nat Commun. 2023 Dec 16. 14(1): 8381
    Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis.
    Nadege Gitego, Bogos Agianian, Oi Wei Mak, Vasantha Kumar Mv, Emily H Cheng, Evripidis Gavathiotis.
      The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.
    DOI:  https://doi.org/10.1038/s41467-023-44084-3
  5. Nature. 2024 Jan;625(7993): 35-36
    Muscle immune cells protect mitochondrial organelles during exercise.
    Gerald Coulis, S Armando Villalta.
      
    Keywords:  Cell biology; Immunology; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-03972-w
  6. Nat Cell Biol. 2023 Dec 21.
    Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network.
    Richard G Lee, Danielle L Rudler, Samuel A Raven, Liuyu Peng, Anaëlle Chopin, Edward S X Moh, Tim McCubbin, Stefan J Siira, Samuel V Fagan, Nicholas J DeBono, Maike Stentenbach, Jasmin Browne, Filip F Rackham, Ji Li, Kaylene J Simpson, Esteban Marcellin, Nicolle H Packer, Gavin E Reid, Benjamin S Padman, Oliver Rackham, Aleksandra Filipovska.
      The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology and reduce respiration. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised, and that the resulting mitochondrial dysfunction can be rescued with precursors for ether-glycerophospholipid metabolic pathways. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease.
    DOI:  https://doi.org/10.1038/s41556-023-01297-4
  7. Leukemia. 2023 Dec 15.
    DELE1 haploinsufficiency causes resistance to mitochondrial stress-induced apoptosis in monosomy 5/del(5q) AML.
    Jean-François Spinella, Jalila Chagraoui, Céline Moison, Vincent P Lavallée, Isabel Boivin, Deanne Gracias, Sylvie Lavallée, Guillaume Richard Carpentier, François Beliveau, Josée Hébert, Guy Sauvageau.
      Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.
    DOI:  https://doi.org/10.1038/s41375-023-02107-4
  8. Mil Med Res. 2023 Dec 19. 10(1): 66
    Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury.
    Chang-Hong Du, Yi-Ding Wu, Ke Yang, Wei-Nian Liao, Li Ran, Chao-Nan Liu, Shu-Zhen Zhang, Kuan Yu, Jun Chen, Yong Quan, Mo Chen, Ming-Qiang Shen, Hong Tang, Shi-Lei Chen, Song Wang, Jing-Hong Zhao, Tian-Min Cheng, Jun-Ping Wang.
      BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive.METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors.
    RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR.
    CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
    Keywords:  Megakaryocytes (MKs); Platelet hyperreactivity; Platelet size; Radiation injury; Thrombocytopenia
    DOI:  https://doi.org/10.1186/s40779-023-00499-z
  9. Mol Cell. 2023 Dec 12. pii: S1097-2765(23)00977-2. [Epub ahead of print]
    The competitive landscape of the dsRNA world.
    Kyle A Cottrell, Ryan J Andrews, Brenda L Bass.
      The ability to sense and respond to infection is essential for life. Viral infection produces double-stranded RNAs (dsRNAs) that are sensed by proteins that recognize the structure of dsRNA. This structure-based recognition of viral dsRNA allows dsRNA sensors to recognize infection by many viruses, but it comes at a cost-the dsRNA sensors cannot always distinguish between "self" and "nonself" dsRNAs. "Self" RNAs often contain dsRNA regions, and not surprisingly, mechanisms have evolved to prevent aberrant activation of dsRNA sensors by "self" RNA. Here, we review current knowledge about the life of endogenous dsRNAs in mammals-the biosynthesis and processing of dsRNAs, the proteins they encounter, and their ultimate degradation. We highlight mechanisms that evolved to prevent aberrant dsRNA sensor activation and the importance of competition in the regulation of dsRNA sensors and other dsRNA-binding proteins.
    Keywords:  ADAR; DHX9; MDA5; PKR; RIG-I; antiviral; dsRNA-binding proteins; innate immunity; interferon
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.033
  10. J Hazard Mater. 2023 Dec 12. pii: S0304-3894(23)02503-7. [Epub ahead of print]465 133219
    Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation.
    Kai Fan, Nuo Dong, Meichai Fang, Zixun Xiang, Lan Zheng, Mengyuan Wang, Yukuan Shi, Gang Tan, Cheng Li, Yuhua Xue.
      Ozone is a common air pollutant associated with various human diseases. The human ocular surface is frequently exposed to ozone in the troposphere, but the mechanisms by which ozone affects the ocular surface health remain unclear. This study aimed to establish a mouse model to investigate the effects of ozone exposure on the ocular surface and the corneal epithelium. The findings revealed that ozone exposure disrupted corneal epithelial homeostasis and differentiation, resulting in corneal squamous metaplasia. Further, ozone exposure induced oxidative damage and cytoplasmic leakage of mitochondrial DNA (mtDNA), thereby activating the cGAS/STING signaling pathway. The activation of the cGAS/STING signaling pathway triggered the activation of downstream NF-κB and TRAF6 signaling pathways, causing corneal inflammation, thereby promoting corneal inflammation and squamous metaplasia. Finally, C-176, a selective STING inhibitor, effectively prevented and treated corneal inflammation and squamous metaplasia caused by ozone exposure. This study revealed the role of mtDNA leakage-mediated cGAS/STING activation in corneal squamous epithelial metaplasia caused by ozone exposure. It also depicted the abnormal expression pattern of corneal epithelial keratin using three-dimensional images, providing new targets and strategies for preventing and treating corneal squamous metaplasia and other ocular surface diseases.
    Keywords:  CGAS/STING; MtDNA; Ozone; Squamous metaplasia
    DOI:  https://doi.org/10.1016/j.jhazmat.2023.133219
  11. Int J Mol Sci. 2023 Dec 12. pii: 17413. [Epub ahead of print]24(24):
    Spontaneous Mutations in Saccharomyces cerevisiae mtDNA Increase Cell-to-Cell Variation in mtDNA Amount.
    Elena Yu Potapenko, Nataliia D Kashko, Dmitry A Knorre.
      In a eukaryotic cell, the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) is usually maintained within a specific range. This suggests the presence of a negative feedback loop mechanism preventing extensive mtDNA replication and depletion. However, the experimental data on this hypothetical mechanism are limited. In this study, we suggested that deletions in mtDNA, known to increase mtDNA abundance, can disrupt this mechanism, and thus, increase cell-to-cell variance in the mtDNA copy numbers. To test this, we generated Saccharomyces cerevisiae rho- strains with large deletions in the mtDNA and rho0 strains depleted of mtDNA. Given that mtDNA contributes to the total DNA content of exponentially growing yeast cells, we showed that it can be quantified in individual cells by flow cytometry using the DNA-intercalating fluorescent dye SYTOX green. We found that the rho- mutations increased both the levels and cell-to-cell heterogeneity in the total DNA content of G1 and G2/M yeast cells, with no association with the cell size. Furthermore, the depletion of mtDNA in both the rho+ and rho- strains significantly decreased the SYTOX green signal variance. The high cell-to-cell heterogeneity of the mtDNA amount in the rho- strains suggests that mtDNA copy number regulation relies on full-length mtDNA, whereas the rho- mtDNAs partially escape this regulation.
    Keywords:  cell cycle; cell-to-cell heterogeneity; deletions; genetic drift; mtDNA; yeast
    DOI:  https://doi.org/10.3390/ijms242417413
  12. Cells. 2023 Dec 07. pii: 2782. [Epub ahead of print]12(24):
    Single-Cell Radiation Response Scoring with the Deep Learning Algorithm CeCILE 2.0.
    Sarah Rudigkeit, Judith Reindl.
      External stressors, such as ionizing radiation, have massive effects on life, survival, and the ability of mammalian cells to divide. Different types of radiation have different effects. In order to understand these in detail and the underlying mechanisms, it is essential to study the radiation response of each cell. This allows abnormalities to be characterized and laws to be derived. Tracking individual cells over several generations of division generates large amounts of data that can no longer be meaningfully analyzed by hand. In this study, we present a deep-learning-based algorithm, CeCILE (Cell classification and in vitro lifecycle evaluation) 2.0, that can localize, classify, and track cells in live cell phase-contrast videos. This allows conclusions to be drawn about the viability of the cells, the cell cycle, cell survival, and the influence of X-ray radiation on these. Furthermore, radiation-specific abnormalities during division could be characterized. In summary, CeCILE 2.0 is a powerful tool to characterize and quantify the cellular response to external stressors such as radiation and to put individual responses into a larger context. To the authors knowledge, this is the first algorithm with a fully integrated workflow that is able to do comprehensive single-cell and cell composite analysis, allowing them to draw conclusions on cellular radiation response.
    Keywords:  cell survival; cell viability; deep learning; phase-contrast; single-cell response
    DOI:  https://doi.org/10.3390/cells12242782
  13. Antioxidants (Basel). 2023 Dec 13. pii: 2105. [Epub ahead of print]12(12):
    Mitochondrial Stress Links Environmental Triggers with Pro-Inflammatory Signaling in Crohn's Disease.
    Flores Martín-Reyes, Manuel Bernal, Cristina Rodríguez-Díaz, Damaris Rodríguez-de Los Reyes, Ailec Ho-Plagaro, Francisca Rodríguez-Pacheco, Laura Camacho-Martel, Raquel Camargo-Camero, Francisco J Rodríguez-González, Guillermo Alcain-Martínez, Rafael Martín-Masot, Víctor M Navas-López, Marina Villanueva-Paz, María Isabel Lucena, Eduardo García-Fuentes, Carlos López-Gómez.
      Inflammatory Bowel Diseases (IBD) are a group of chronic, inflammatory disorders of the gut. The incidence and activity of IBD are determined by both genetic and environmental factors. Among these factors, polymorphisms in genes related to autophagy and the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have been consistently associated with IBD. We show that NSAIDs induce mitochondrial stress and mitophagy in intestinal epithelial cells. In an altered mitophagy context simulating that observed in IBD patients, NSAID-induced mitochondrial stress leads to the release of mitochondrial components, which act as Danger Associated Molecular Patterns with pro-inflammatory potential. Furthermore, colonic organoids from Crohn's disease patients and healthy donors show activation of the mitochondrial Unfolded Protein Response (UPRmt) upon treatment with ibuprofen. Finally, colon biopsies from Crohn's disease patients in remission or with low-to-moderate activity also show expression of genes involved in UPRmt, while patients with severe activity show no increase compared to healthy donors. Our results suggest the involvement of mitochondria in the mechanisms triggering inflammation in IBD after NSAID use. Moreover, our results highlight the clinical relevance of mitochondrial stress and activation of the UPRmt pathway in the pathophysiology of Crohn's disease.
    Keywords:  Crohn’s disease; inflammatory bowel diseases; mitochondria; mitochondrial unfolded protein response; non-steroidal anti-inflammatory drugs
    DOI:  https://doi.org/10.3390/antiox12122105
  14. Nat Commun. 2023 Dec 20. 14(1): 8455
    Nuclear RPSA senses viral nucleic acids to promote the innate inflammatory response.
    Yan Jiang, Siqi Sun, Yuan Quan, Xin Wang, Yuling You, Xiao Zhang, Yue Zhang, Yin Liu, Bingjing Wang, Henan Xu, Xuetao Cao.
      Innate sensors initiate the production of type I interferons (IFN-I) and proinflammatory cytokines to protect host from viral infection. Several innate nuclear sensors that mainly induce IFN-I production have been identified. Whether there exist innate nuclear sensors that mainly induce proinflammatory cytokine production remains to be determined. By functional screening, we identify 40 S ribosomal protein SA (RPSA) as a nuclear protein that recognizes viral nucleic acids and predominantly promotes proinflammatory cytokine gene expression in antiviral innate immunity. Myeloid-specific Rpsa-deficient mice exhibit less innate inflammatory response against infection with Herpes simplex virus-1 (HSV-1) and Influenza A virus (IAV), the viruses replicating in nucleus. Mechanistically, nucleus-localized RPSA is phosphorylated at Tyr204 upon infection, then recruits ISWI complex catalytic subunit SMARCA5 to increase chromatin accessibility of NF-κB to target gene promotors without affecting innate signaling. Our results add mechanistic insights to an intra-nuclear way of initiating proinflammatory cytokine expression in antiviral innate defense.
    DOI:  https://doi.org/10.1038/s41467-023-43784-0
  15. Viruses. 2023 Nov 30. pii: 2359. [Epub ahead of print]15(12):
    Regulation of Mitochondrial Metabolism by Hepatitis B Virus.
    Yumei Li, Jing-Hsiung James Ou.
      Mitochondria play important roles in the synthesis of ATP, the production of reactive oxygen species, and the regulation of innate immune response and apoptosis. Many viruses perturb mitochondrial activities to promote their replication and cause cell damage. Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). This virus can also alter mitochondrial functions and metabolism to promote its replication and persistence. In this report, we summarize recent research progress on the interaction between HBV and mitochondrial metabolism, as well as the effect this interaction has on HBV replication and persistence.
    Keywords:  CD8+ T cells; hepatic macrophages; hepatitis B virus; innate immune response; mitochondrial metabolism; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/v15122359
  16. Open Biol. 2023 Dec;13(12): 230181
    Mitochondrial replication's role in vertebrate mtDNA strand asymmetry.
    André Gomes-Dos-Santos, Nair Vilas-Arrondo, André M Machado, Esther Román-Marcote, Jose Luís Del Río Iglesias, Francisco Baldó, Montse Pérez, Miguel M Fonseca, L Filipe C Castro, Elsa Froufe.
      Mitogenomes are defined as compact and structurally stable over aeons. This perception results from a vertebrate-centric vision, where few types of mtDNA rearrangements are described. Here, we bring a new light to the involvement of mitochondrial replication in the strand asymmetry of the vertebrate mtDNA. Using several species of deep-sea hatchetfish (Sternoptychidae) displaying distinct mtDNA structural arrangements, we unravel the inversion of the coding direction of protein-coding genes (PCGs). This unexpected change is coupled with a strand asymmetry nucleotide composition reversal and is shown to be directly related to the strand location of the Control Region (CR). An analysis of the fourfold redundant sites of the PCGs (greater than 6000 vertebrates), revealed the rarity of this phenomenon, found in nine fish species (five deep-sea hatchetfish). Curiously, in Antarctic notothenioid fishes (Trematominae), where a single PCG inversion (the only other record in fish) is coupled with the inversion of the CR, the standard asymmetry is disrupted for the remaining PCGs but not yet reversed, suggesting a transitory state. Our results hint that a relaxation of the classic vertebrate mitochondrial structural stasis promotes disruption of the natural balance of asymmetry of the mtDNA. These findings support the long-lasting hypothesis that replication is the main molecular mechanism promoting the strand-specific compositional bias of this unique and indispensable molecule.
    Keywords:  deep-sea fish; mitochondrial gene order; mitogenome; rearrangements; strand asymmetry
    DOI:  https://doi.org/10.1098/rsob.230181
  17. bioRxiv. 2023 Dec 10. pii: 2023.12.09.569632. [Epub ahead of print]
    Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology.
    Sunita Maharjan, Howard Gamper, Yuka Yamaki, Robert Y Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A Piccirilli, Meni Wanunu, Erin Seifert, Douglas C Wallace, Ya-Ming Hou.
      Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA structure would also stabilize its pathogenic variants is unknown. Here we show that the N 1 -methylation of guanosine at position 9 (m 1 G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m 1 G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that the N 1 -methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
    DOI:  https://doi.org/10.1101/2023.12.09.569632
  18. ACS Omega. 2023 Dec 12. 8(49): 46438-46449
    Irradiation Induces Gasdermin E-Triggered Tumor Immunity to Inhibit Esophageal Carcinoma Cell Survival.
    Bingxu Tan, Nana Wang, Shengsi Yang, Hui Liu, Yufeng Cheng.
      Gasdermin E (GSDME), an executor of pyroptosis, can be activated by caspase-3 and has been recognized as a tumor suppressor in various human cancers. In addition, caspase-3/GSDME signal-induced pyroptosis is a form of immunogenic cell death (ICD). In this study, we aimed to understand the association between radiotherapy and caspase-3/GSDME signal-related ICD in esophageal carcinoma (EC) cells. The expression of caspase-3 and GSDME in two EC cell lines, ECA-109 and KYSE-150, was silenced or overexpressed by transfection with specific siRNAs or overexpression vectors. Cells were subjected to 0-8 Gy irradiation, and cell death was evaluated by CCK-8 assay, annexin V-FITC staining, lactate dehydrogenase (LDH) detection kit, Western blotting, and immunofluorescence. Irradiation in both EC cell lines promoted dose-dependent viability loss and apoptosis. More specifically, 8 Gy X-ray increased the apoptosis rate from 4.1 to 12.8% in ECA-109 cells and from 4.6 to 21.1% in KYSE-150 cells. In irradiated EC cells, the levels of LDH release and caspase-3/GSDME cleavage were increased. Caspase-3 silencing inhibited irradiation-induced GSDME cleavage and EC cell death. Furthermore, we identified the death of EC cells suppressed by caspase-3 siRNA, and the levels of CRT, HMGB1, HSP70, and HSP90 were also markedly downregulated by caspase-3 siRNA. Similarly, GSDME silencing diminished irradiation-induced EC cell death and the levels of ICD markers. Overexpression of caspase-3 and GSDME accelerated irradiation-induced ICD. In summary, irradiation in EC cells induces GSDME-mediated pyroptosis and activates ICD to inhibit esophageal carcinoma cell survival.
    DOI:  https://doi.org/10.1021/acsomega.3c03791
  19. Neural Regen Res. 2024 Aug 01. 19(8): 1828-1834
    A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.
    Yongjiang Zhang, Shiyi Yin, Run Song, Xiaoyi Lai, Mengmeng Shen, Jiannan Wu, Junqiang Yan.
      JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.
    DOI:  https://doi.org/10.4103/1673-5374.389356
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