bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–11–17
twenty-one papers selected by
Marco Tigano, Thomas Jefferson University
  1. Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
  2. FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.
  3. Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.
  4. Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
  5. A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
  6. Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
  7. Dysfunctional RNA binding protein induced neurodegeneration is attenuated by inhibition of the integrated stress response.
  8. Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
  9. Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
  10. The Warburg Effect is the result of faster ATP production by glycolysis than respiration.
  11. Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
  12. Opposing roles for AMPK in regulating distinct mitophagy pathways.
  13. N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.
  14. The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
  15. Autophagy-dependent splicing control directs translation toward inflammation during senescence.
  16. Age-related STING suppression in macrophages contributes to increased viral load during influenza a virus infection.
  17. Targeting PRMT7-mediated monomethylation of MAVS enhances antiviral innate immune responses and inhibits RNA virus replication.
  18. Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging.
  19. The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma.
  20. Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.
  21. PunctaFinder: an algorithm for automated spot detection in fluorescence microscopy images.
  1. Mol Biol Cell. 2024 Nov 13. mbcE24070306
    Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
    Brett T Wisniewski, Jason C Casler, Laura L Lackner.
      Mitochondria exist as dynamic tubular networks and the morphology of these networks impacts organelle function and cell health. Mitochondrial morphology is maintained in part by the opposing activities of mitochondrial fission and fusion. Mitochondrial fission and fusion are also required to maintain mitochondrial DNA (mtDNA) integrity. In Saccharomyces cerevisiae, the simultaneous inhibition of mitochondrial fission and fusion results in increased mtDNA mutation and the consequent loss of respiratory competence. The mechanism by which fission and fusion maintain mtDNA integrity is not fully understood. Previous work demonstrates that mtDNA is spatially linked to mitochondrial fission sites. Here, we extend this finding using live-cell imaging to localize mtDNA to mitochondrial fusion sites. While mtDNA is present at sites of mitochondrial fission and fusion, mitochondrial fission and fusion rates are not altered in cells lacking mtDNA. Using alleles that alter mitochondrial fission and fusion rates, we find that mtDNA integrity can be maintained in cells with significantly reduced, but balanced, rates of fission and fusion. In addition, we find that increasing mtDNA copy number reduces the loss of respiratory competence in double mitochondrial fission-fusion mutants. Our findings add novel insights into the relationship between mitochondrial dynamics and mtDNA integrity.
    DOI:  https://doi.org/10.1091/mbc.E24-07-0306
  2. Nat Cell Biol. 2024 Nov 15.
    FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.
    Adam R Fenton, Ruchao Peng, Charles Bond, Siewert Hugelier, Melike Lakadamyali, Yi-Wei Chang, Erika L F Holzbaur, Thomas A Jongens.
      Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission.
    DOI:  https://doi.org/10.1038/s41556-024-01544-2
  3. EMBO J. 2024 Nov 08.
    Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.
    Genís Valentín Gesé, B Martin Hällberg.
      Maturation of human mitochondrial tRNA is essential for cellular energy production, yet the underlying mechanisms remain only partially understood. Here, we present several cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to different maturation states of mitochondrial tRNAHis, showing the molecular basis for tRNA-substrate selection and catalysis. Our structural insights provide a molecular rationale for the 5'-to-3' tRNA processing order in mitochondria, the 3'-CCA antideterminant effect, and the basis for sequence-independent recognition of mitochondrial tRNA substrates. Furthermore, our study links mutations in ELAC2 to clinically relevant mitochondrial diseases, offering a deeper understanding of the molecular defects contributing to these conditions.
    Keywords:  Cryo-EM; ELAC2; Mitochondria; RNA Processing; RNase Z
    DOI:  https://doi.org/10.1038/s44318-024-00297-w
  4. Metabolism. 2024 Nov 06. pii: S0026-0495(24)00289-0. [Epub ahead of print] 156061
    Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
    Francesca Pontanari, Hadrien Demagny, Adrien Faure, Xiaoxu Li, Giorgia Benegiamo, Antoine Jalil, Alessia Perino, Johan Auwerx, Kristina Schoonjans.
      Several laboratories, including ours, have employed the Slc25a47tm1c(EUCOMM)Hmgu mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1, a cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses.
    Keywords:  Hepatocytes; ISR; MSR; SLC25A47; Translation; UPR(mt); WARS1
    DOI:  https://doi.org/10.1016/j.metabol.2024.156061
  5. Autophagy. 2024 Nov 09.
    A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
    Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su.
      PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of Rnf7 in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.
    Keywords:  Heart failure; RBX2/SAG; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2423329
  6. Nat Cell Biol. 2024 Nov 13.
    Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
    Christos Kiourtis, Maria Terradas-Terradas, Lucy M Gee, Stephanie May, Anastasia Georgakopoulou, Amy L Collins, Eoin D O'Sullivan, David P Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H Reed, Lee A Borthwick, Colin Nixon, William Clark, Peter S Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K Najumudeen, Gareth J Inman, Andrew Campbell, Simon T Barry, Alberto Quaglia, Christopher M Morris, Fiona E N LeBeau, Owen J Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G Bird.
      Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01543-3
  7. Biochim Biophys Acta Mol Basis Dis. 2024 Nov 07. pii: S0925-4439(24)00556-8. [Epub ahead of print]1871(1): 167562
    Dysfunctional RNA binding protein induced neurodegeneration is attenuated by inhibition of the integrated stress response.
    Joseph-Patrick W E Clarke, Miranda L Messmer, Jacob Pilon, Jenna Reding, Patricia A Thibault, Hannah E Salapa, Michael C Levin.
      Dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributes to neurodegeneration, the primary cause of permanent disability in multiple sclerosis (MS). To better understand the role of hnRNP A1 dysfunction in the pathogenesis of neurodegeneration, we utilized optogenetics-driven hnRNP A1 clustering to model its dysfunction in neuron-like differentiated Neuro-2A cells. hnRNP A1 clustering activates the integrated stress response (ISR) and results in a neurodegenerative phenotype marked by decreased neuronal protein translation and neurite loss. Small molecule inhibition of the ISR with either PERKi (GSK2606414) or ISRIB (integrated stress response inhibitor) attenuated both the decrease in neuronal translation and neurite loss, without affecting hnRNP A1 clustering. We then confirmed a strong association between hnRNP A1 clustering and ISR activation in neurons from MS brains. These data illustrate that hnRNP A1 dysfunction promotes neurodegeneration by activation of the ISR in vitro and in vivo, thus revealing a novel therapeutic target to reduce neurodegeneration and subsequent disability in MS.
    Keywords:  Cell stress inhibition; HNRNPA1; Neurite loss; Optogenetics; Protein clustering; Protein translation
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167562
  8. Autophagy. 2024 Nov 08.
    Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
    Moumita Roy, Sumangal Nandy, Elena Marchesan, Chayan Banerjee, Rupsha Mondal, Federico Caicci, Elena Ziviani, Joy Chakraborty.
      Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this phenomenon. Through in vitro biochemical assays and imaging, we have found that VDAC1-PHB2 interaction increases during mitochondrial depolarization. Subsequently, this interaction enhances the efficiency of PHB2 exposure and mitophagy. To investigate the relevance in vivo, we utilized porin (equivalent to VDAC1) knockout Drosophila line. Our findings demonstrate that during mitochondrial stress, porin is essential for Phb2 exposure, Phb2-Atg8 interaction and mitophagy. This study highlights that VDAC1 predominantly synchronizes efficient PHB2 exposure through mitochondrial rupture sites during mitophagy. These findings may provide insights to understand progressive neurodegeneration.
    Keywords:  Neurodegeneration; PHB2-LC3 interaction; PINK1-PRKN; parkinson disease; porin; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2024.2426116
  9. Sci Rep. 2024 11 08. 14(1): 27182
    Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
    Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.
      Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.
    Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes
    DOI:  https://doi.org/10.1038/s41598-024-78434-y
  10. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2409509121
    The Warburg Effect is the result of faster ATP production by glycolysis than respiration.
    Matthew A Kukurugya, Saharon Rosset, Denis V Titov.
      Many prokaryotic and eukaryotic cells metabolize glucose to organism-specific by-products instead of fully oxidizing it to carbon dioxide and water-a phenomenon referred to as the Warburg Effect. The benefit to a cell is not fully understood, given that partial metabolism of glucose yields an order of magnitude less adenosine triphosphate (ATP) per molecule of glucose than complete oxidation. Here, we test a previously formulated hypothesis that the benefit of the Warburg Effect is to increase ATP production rate by switching from high-yielding respiration to faster glycolysis when excess glucose is available and respiration rate becomes limited by proteome occupancy. We show that glycolysis produces ATP faster per gram of pathway protein than respiration in Escherichia coli, Saccharomyces cerevisiae, and mammalian cells. We then develop a simple mathematical model of energy metabolism that uses five experimentally estimated parameters and show that this model can accurately predict absolute rates of glycolysis and respiration in all three organisms under diverse conditions, providing strong support for the validity of the ATP production rate maximization hypothesis. In addition, our measurements show that mammalian respiration produces ATP up to 10-fold slower than respiration in E. coli or S. cerevisiae, suggesting that the ATP production rate per gram of pathway protein is a highly evolvable trait that is heavily optimized in microbes. We also find that E. coli respiration is faster than fermentation, explaining the observation that E. coli, unlike S. cerevisiae or mammalian cells, never switch to pure fermentation in the presence of oxygen.
    Keywords:  Warburg Effect; cancer metabolism; energy metabolism; modeling; systems biology
    DOI:  https://doi.org/10.1073/pnas.2409509121
  11. J Transl Med. 2024 Nov 11. 22(1): 1012
    Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
    Yinghua Wang, Xiying Huang, Huanhuan Huo, Zhaohua Cai, Qingqi Ji, Yi Jiang, Fei Zhuang, Yi Li, Linghong Shen, Xia Wang, Ben He.
       AIM: Mitochondrial dysfunction is a critical factor in the pathogenesis of septic cardiomyopathy (SCM). Mitochondrial anchored protein ligase (MAPL), a small ubiquitin-like modifier (SUMO) E3 ligase, plays a significant role in mitochondrial function. However, the role of MAPL in SCM remains unclear.
    METHODS: To investigate the role of MAPL in SCM, cardiomyocyte-specific MAPL knockout mice were generated. A cecal ligation and puncture (CLP) procedure was employed to induce a sepsis-like condition.
    RESULTS: The expression of MAPL in heart tissues and H9C2 cardiomyocytes was elevated following CLP challenge or lipopolysaccharide (LPS) stimulation. MAPL deficiency ameliorated CLP-induced cardiac injury, dysfunction, and inflammation, and also improved the survival rate of mice following CLP operation. Additionally, MAPL deficiency or knockdown inhibited LPS-induced cardiomyocyte apoptosis, improved mitochondrial structural abnormalities, and increased ATP production. Furthermore, MAPL knockdown mitigated LPS-induced reductions in mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production. Mechanistically, the expression of dynamin-related protein 1 (drp1) in the mitochondria of heart tissues or H9C2 cardiomyocytes was elevated under septic conditions. Accordingly, the SUMOylation of drp1 in heart tissues or H9C2 cardiomyocytes was increased under sepsis conditions, which was reduced by MAPL knockout or knockdown.
    CONCLUSION: Our results reveal that MAPL promotes cardiac injury/dysfunction and inflammation in SCM. Deficiency or knockdown of MAPL alleviates SCM by reducing drp1 SUMOylation as well as drp1-mediated mitochondrial dysfunction. These findings suggest that targeting MAPL may represent a therapeutic strategy for patients with SCM.
    Keywords:  MAPL; Mitochondria; SUMOylation; Septic cardiomyopathy
    DOI:  https://doi.org/10.1186/s12967-024-05836-x
  12. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]
    Opposing roles for AMPK in regulating distinct mitophagy pathways.
    Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.
      Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
    Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
  13. Commun Biol. 2024 Nov 11. 7(1): 1486
    N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.
    Gabriele Coluccino, Alessandro Negro, Antonio Filippi, Camilla Bean, Valentina Pia Muraca, Clarissa Gissi, Diana Canetti, Maria Chiara Mimmi, Elisa Zamprogno, Francesco Ciscato, Laura Acquasaliente, Vincenzo De Filippis, Marina Comelli, Michela Carraro, Andrea Rasola, Christoph Gerle, Paolo Bernardi, Alessandra Corazza, Giovanna Lippe.
      Cyclophilin (CyP) D is a regulator of the mitochondrial F-ATP synthase. Here we report the discovery of a form of CyPD lacking the first 10 (mouse) or 13 (human) N-terminal residues (ΔN-CyPD), a protein region with species-specific features. NMR studies on recombinant human full-length CyPD (FL-CyPD) and ΔN-CyPD form revealed that the N-terminus is highly flexible, in contrast with the rigid globular part. We have studied the interactions of FL and ΔN-CyPD with F-ATP synthase at the OSCP subunit, a site where CyPD binding inhibits catalysis and favors the transition of the enzyme complex to the permeability transition pore. At variance from FL-CyPD, ΔN-CyPD binds OSCP in saline media, indicating that the N-terminus substantially decreases the binding affinity for OSCP. We also provide evidence that calpain 1 is responsible for generation of ΔN-CyPD in cells. Altogether, our work suggests the existence of a novel mechanism of modulation of CyPD through cleavage of its N-terminus that may have significant pathophysiological implications.
    DOI:  https://doi.org/10.1038/s42003-024-07172-8
  14. Nat Commun. 2024 Nov 13. 15(1): 9826
    The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
    Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de Almeida, Thomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow.
      Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.
    DOI:  https://doi.org/10.1038/s41467-024-54183-4
  15. Dev Cell. 2024 Nov 01. pii: S1534-5807(24)00627-0. [Epub ahead of print]
    Autophagy-dependent splicing control directs translation toward inflammation during senescence.
    Jaejin Kim, Yeonghyeon Lee, Taerang Jeon, Seonmin Ju, Jong-Seo Kim, Mi-Sung Kim, Chanhee Kang.
      The cellular proteome determines the functional state of cells and is often skewed to direct pathological conditions. Autophagy shapes cellular proteomes primarily through lysosomal degradation of either damaged or unnecessary proteins. Here, we show that autophagy directs the senescence-specific translatome to fuel inflammation by coupling selective protein degradation with alternative splicing. RNA splicing is significantly altered during senescence, some of which surprisingly depend on autophagy, including exon 5 skipping of the translation regulator EIF4H. Systematic translatome profiling indicates that this event is key to the translational bias toward inflammation in senescence. Autophagy promotes these changes by selectively degrading the splicing regulator splicing factor proline and glutamine rich (SFPQ) via the autophagy receptor NBR1. These autophagy-centric inflammatory controls appear to be conserved during human tissue aging and cancer. Our work highlights the role of autophagy in the on-demand functional remodeling of cellular proteomes as well as the crosstalk between autophagy, alternative splicing, and inflammatory translation.
    Keywords:  RNA homeostasis; aging; alternative splicing; autophagy; cancer; cellular senescence; inflammation; protein translation; selective autophagy
    DOI:  https://doi.org/10.1016/j.devcel.2024.10.008
  16. Immun Ageing. 2024 Nov 14. 21(1): 80
    Age-related STING suppression in macrophages contributes to increased viral load during influenza a virus infection.
    Thurid Lauf, Antje Häder, Franziska Hornung, Yasmina Reisser, Sandor Nietzsche, Fabian Schanz, Verena Trümper, Aldona Jeznach, Sascha Brunke, Torsten Doenst, Tomasz Skirecki, Bettina Löffler, Stefanie Deinhardt-Emmer.
      Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains. Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production by applying a THP-1 STING knockout model. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling. Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.
    Keywords:  Ageing; Influenza A virus; Macrophages; Mitochondria; cGAS-STING pathway
    DOI:  https://doi.org/10.1186/s12979-024-00482-9
  17. Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2408117121
    Targeting PRMT7-mediated monomethylation of MAVS enhances antiviral innate immune responses and inhibits RNA virus replication.
    Jingjing Yang, Wenjuan Li, Zepeng Zhang, Xiaohua Gong, Yanchao Chen, Xiaoyu Peng, Guosheng Hu, Xianglong Dai, Yaohui He, Ying Huang, Shiqiang Cao, Yang Yang, Wen Liu.
      RIG-I-like receptors (RLRs)-mitochondrial antiviral signaling protein (MAVS) are crucial for type I interferon (IFN) signaling pathway and innate immune responses triggered by RNA viruses. However, the regulatory molecular mechanisms underlying RNA virus-activated type I IFN signaling pathway remain incompletely understood. Here, we found that protein arginine methyltransferase 7 (PRMT7) serves as a negative regulator of the type I IFN signaling pathway by interacting with MAVS and catalyzing monomethylation of arginine 232 (R232me1) in MAVS. RNA virus infection leads to the downregulation and dissociation of PRMT7 from MAVS as well as the decrease of R232me1 methylation, enhancing MAVS/RIG-I interaction, MAVS aggregation, type I IFN signaling activation, and antiviral immune responses. Knock-in mice with MAVS R232 substituted with lysine (MavsR232K-KI) are more resistant to Vesicular Stomatitis Virus infection due to enhanced antiviral immune responses. PiPRMT7-MAVS, a short peptide inhibitor designed to interrupt the interaction between PRMT7 and MAVS, inhibits R232me1 methylation, thereby enhancing MAVS/RIG-I interaction, promoting MAVS aggregation, activating type I IFN signaling, and bolstering antiviral immune responses to suppress RNA virus replication. Moreover, the clinical relevance of PRMT7 is highlighted that it is significantly downregulated in RNA virus-infected clinical samples, such as blood samples from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus, as well as H1N1-infected bronchial epithelial cells. Our findings uncovered that PRMT7-mediated arginine methylation plays critical roles in regulating MAVS-mediated antiviral innate immune responses, and targeting arginine methylation might represent a therapeutic avenue for treating RNA viral infection.
    Keywords:  RNA virus; antiviral innate immune responses; arginine methylation; epigenetic regulation
    DOI:  https://doi.org/10.1073/pnas.2408117121
  18. Nat Aging. 2024 Nov 14.
    Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging.
    Jian Mao, Qian Zhang, Yang Zhuang, Yinyu Zhang, Linmeng Li, Juan Pan, Lu Xu, Yuxuan Ding, Miao Wang, Yu-Sheng Cong.
      Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5-MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson-Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFNβ in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging.
    DOI:  https://doi.org/10.1038/s43587-024-00745-6
  19. Cancer Res. 2024 Nov 12.
    The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma.
    Yijian Zhang, Xuming Song, Yipeng Feng, Yuxian Qian, Bing Chen, Te Zhang, Hui Wang, Yuzhong Chen, Xinnian Yu, Hanlin Ding, Rutao Li, Pengfe Ge, Lin Xu, Gaochao Dong, Feng Jiang.
      Immunogenic cell death (ICD) induces an active immune response. Activating ICD represents a potential approach to boost the anti-tumor activity of immunotherapy, highlighting the need to identify effective and safe ICD inducers. In this study, we identified a conserved, ICD-related circular RNA cEMSY by systematically screening ICD models induced by multiple cell stressors in lung adenocarcinoma (LUAD). cEMSY triggered ICD in LUAD both in vitro and in vivo, leading to the release of damage-associated molecular patterns and promoting T cell cross-priming by dendritic cells (DCs). Notably, the intratumoral delivery of lipid nanoparticle-encapsulated cEMSY induced a potent antitumor immune response in an immunosuppressed tumor model, which synergized with PD-1 blockade to facilitate long-term anti-tumor immunity with no apparent toxicities. Mechanistically, cEMSY mediated mitochondrial aggregation of the RNA-binding protein TDP-43 that enabled leakage of mitochondrial DNA to stimulate the cGAS-STING pathway, activating the antiviral immune response. Clinically, elevated expression of cEMSY correlated with enhanced infiltration of DCs and CD8+ T cells and favorable immunotherapy response in LUAD. Together, these findings support the dual potential of cEMSY as a target and biomarker for improving immune checkpoint inhibitor responses in LUAD.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1484
  20. Adv Sci (Weinh). 2024 Nov 08. e2404109
    Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.
    Yujiao He, Yanchen Liu, Mingyue Zheng, Yuxiu Zou, Mujie Huang, Linsheng Wang, Ge Gao, Zhongjun Zhou, Guoxiang Jin.
      Targeting cellular senescence, one of the hallmarks of aging and aging-related pathologies emerges as an effective strategy for anti-aging and cancer chemotherapy. Here, a switch from TBK1-OPTN axis to TBK1-ATAD3A axis to promote cellular senescence is shown. Mechanically, TBK1 protein is abnormally activated and localized to the mitochondria during senescence, which directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A is significantly elevated in cellular senescence as well as in physiological and pathological aging and is essential for suppressing Pink1-mediated mitophagy by facilitating Pink1 mitochondrial import. Inhibition of ATAD3A phosphorylation at Ser321 by either TBK1 deficiency or by a Ser321A mutation rescues the cellular senescence. A blocking peptide, TAT-PEP, specifically abrogating ATAD3A phosphorylation, results in elevated cell death by preventing doxorubicin-induced senescence, thus leading to enhanced tumor sensitivity to chemotherapy. TAT-PEP treatment also ameliorates various phenotypes associated with physiological aging. Collectively, these results reveal the TBK1-ATAD3A-Pink1 axis as a driving force in cellular senescence and suggest a potential mitochondrial target for anti-aging therapy.
    Keywords:  TBK1‐ATAD3A axis; anti‐aging therapy; cellular senescence; chemotherapy; mitophagy
    DOI:  https://doi.org/10.1002/advs.202404109
  21. Mol Biol Cell. 2024 Nov 13. mbcE24060254
    PunctaFinder: an algorithm for automated spot detection in fluorescence microscopy images.
    Hanna M Terpstra, Rubén Gómez-Sánchez, Annemiek C Veldsink, Tegan A Otto, Liesbeth M Veenhoff, Matthias Heinemann.
      Fluorescence microscopy has revolutionised biological research by enabling the visualisation of subcellular structures at high resolution. With the increasing complexity and volume of microscopy data, there is a growing need for automated image analysis to ensure efficient and consistent interpretation. In this study, we introduce PunctaFinder, a novel Python-based algorithm designed to detect puncta, small bright spots, in raw fluorescence microscopy images without image denoising or signal enhancement steps. Furthermore, unlike other available spot detectors, PunctaFinder not only detects puncta, but also defines the cytoplasmic region, making it a valuable tool to quantify target molecule localisation in cellular contexts. PunctaFinder is a widely applicable punctum detector and size estimator, as evidenced by its successful detection of Atg9-positive vesicles, lipid droplets, aggregates of a destabilised luciferase mutant, and the nuclear pore complex. Notably, PunctaFinder excels in detecting puncta in images with a relatively low resolution and signal-to-noise ratio, demonstrating its capability to identify dim puncta and puncta of dynamic target molecules. PunctaFinder reliably detects puncta in fluorescence microscopy images where automated analysis was not possible before, providing researchers with an efficient and robust method for punctum quantification in fluorescence microscopy images.
    DOI:  https://doi.org/10.1091/mbc.E24-06-0254
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