bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2021–06–13
25 papers selected by
Hanna Salmonowicz, Newcastle University
  1. Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.
  2. The Role of Mitophagy in Regulating Cell Death.
  3. Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response.
  4. Systematic quantification of the dynamics of newly synthesized proteins unveiling their degradation pathways in human cells.
  5. Should nutritional therapy be modified to account for mitochondrial dysfunction in critical illness?
  6. A link between protein acetylation and mitochondrial dynamics under energy metabolism: A comprehensive overview.
  7. GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage.
  8. Maintenance of complex I and its super-complexes by NDUF-11 is essential for mitochondrial structure, function and health.
  9. The role of Mfn2 in the structure and function of ER-mitochondrial tethering in vivo.
  10. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.
  11. Integrated signaling system under endoplasmic reticulum stress in eukaryotic microorganisms.
  12. Mitochondria: Their relevance during oocyte ageing.
  13. Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes.
  14. Apoptotic signals at the endoplasmic reticulum-mitochondria interface.
  15. Optimizing mitochondrial maintenance in extended neuronal projections.
  16. Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages.
  17. SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation.
  18. Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents.
  19. Bacterial RF3 senses chaperone function in co-translational folding.
  20. An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial membrane.
  21. The role of T cells in age-related diseases.
  22. Interferon regulatory factor 7 impairs cellular metabolism in aging adipose-derived stromal cells.
  23. A hitchhiker's guide to mitochondrial quantification.
  24. Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection.
  25. Early inflammation dysregulates neuronal circuit formation in vivo via upregulation of IL-1β.
  1. Aging Cell. 2021 Jun 07. e13408
    Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.
    Tara R Richman, Judith A Ermer, Stefan J Siira, Irina Kuznetsova, Christopher A Brosnan, Giulia Rossetti, Jessica Baker, Kara L Perks, Henrietta Cserne Szappanos, Helena M Viola, Nicola Gray, Mark Larance, Livia C Hool, Steven Zuryn, Oliver Rackham, Aleksandra Filipovska.
      Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high-fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error-prone (Mrps12ep / ep ) or hyper-accurate (Mrps12ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high-fat diet, they manifest divergent (either deleterious or beneficial) outcomes in a tissue-specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12ha / ha mice protected the liver from a high-fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post-mitotic (heart) and highly proliferative (liver) tissues. We show trade-offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue-specific outcomes due to commonly encountered stressful environmental conditions or aging.
    Keywords:  ageing; metabolism; mitochondria; protein synthesis
    DOI:  https://doi.org/10.1111/acel.13408
  2. Oxid Med Cell Longev. 2021 ;2021 6617256
    The Role of Mitophagy in Regulating Cell Death.
    Sunao Li, Jiaxin Zhang, Chao Liu, Qianliang Wang, Jun Yan, Li Hui, Qiufang Jia, Haiyan Shan, Luyang Tao, Mingyang Zhang.
      Mitochondria are multifaceted organelles that serve to power critical cellular functions, including act as power generators of the cell, buffer cytosolic calcium overload, production of reactive oxygen species, and modulating cell survival. The structure and the cellular location of mitochondria are critical for their function and depend on highly regulated activities such as mitochondrial quality control (MQC) mechanisms. The MQC is regulated by several sets of processes: mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy, and other mitochondrial proteostasis mechanisms such as mitochondrial unfolded protein response (mtUPR) or mitochondrial-derived vesicles (MDVs). These processes are important for the maintenance of mitochondrial homeostasis, and alterations in the mitochondrial function and signaling are known to contribute to the dysregulation of cell death pathways. Recent studies have uncovered regulatory mechanisms that control the activity of the key components for mitophagy. In this review, we discuss how mitophagy is controlled and how mitophagy impinges on health and disease through regulating cell death.
    DOI:  https://doi.org/10.1155/2021/6617256
  3. Life Sci Alliance. 2021 Jul;pii: e202000915. [Epub ahead of print]4(7):
    Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response.
    Onruedee Khantisitthiporn, Byron Shue, Nicholas S Eyre, Colt W Nash, Lynne Turnbull, Cynthia B Whitchurch, Kylie H Van der Hoek, Karla J Helbig, Michael R Beard.
      Peroxisomes are recognized as significant platforms for the activation of antiviral innate immunity where stimulation of the key adapter molecule mitochondrial antiviral signaling protein (MAVS) within the RIG-I like receptor (RLR) pathway culminates in the up-regulation of hundreds of ISGs, some of which drive augmentation of multiple innate sensing pathways. However, whether ISGs can augment peroxisome-driven RLR signaling is currently unknown. Using a proteomics-based screening approach, we identified Pex19 as a binding partner of the ISG viperin. Viperin colocalized with numerous peroxisomal proteins and its interaction with Pex19 was in close association with lipid droplets, another emerging innate signaling platform. Augmentation of the RLR pathway by viperin was lost when Pex19 expression was reduced. Expression of organelle-specific MAVS demonstrated that viperin requires both mitochondria and peroxisome MAVS for optimal induction of IFN-β. These results suggest that viperin is required to enhance the antiviral cellular response with a possible role to position the peroxisome at the mitochondrial/MAM MAVS signaling synapse, furthering our understanding of the importance of multiple organelles driving the innate immune response against viral infection.
    DOI:  https://doi.org/10.26508/lsa.202000915
  4. Chem Sci. 2020 Mar 10. 11(13): 3557-3568
    Systematic quantification of the dynamics of newly synthesized proteins unveiling their degradation pathways in human cells.
    Ming Tong, Johanna M Smeekens, Haopeng Xiao, Ronghu Wu.
      Proteins are continuously synthesized during cell growth and proliferation. At the same time, excessive and misfolded proteins have to be degraded, otherwise they are a burden to cells. Protein degradation is essential to maintain proteostasis in cells, and dysfunction of protein degradation systems results in numerous diseases such as cancer and neurodegenerative diseases. Despite the importance of protein degradation, the degradation pathways of many proteins remain to be explored. Here, we comprehensively investigated the degradation of newly synthesized proteins in human cells by integrating metabolic labeling, click chemistry, and multiplexed proteomics, and systematic and quantitative analysis of newly synthesized proteins first revealed the degradation pathways of many proteins. Bioinformatic analysis demonstrates that proteins degraded through two major pathways have distinct properties and functions. Proteins degraded through the ubiquitin-proteasome pathway contain more disordered structures, whereas those through the autophagy-lysosome pathway have significantly higher hydrophobicity. Systematic and quantitative investigation of the dynamics of newly synthesized proteins provides unprecedented and valuable information about protein degradation, which leads to a better understanding of protein properties and cellular activities.
    DOI:  https://doi.org/10.1039/c9sc06479f
  5. JPEN J Parenter Enteral Nutr. 2021 Jun 11.
    Should nutritional therapy be modified to account for mitochondrial dysfunction in critical illness?
    Luke Flower, Alexandria Page, Zudin Puthucheary.
      Metabolic dysfunction, and its associated muscle atrophy, remains the most common complication of critical care. At the centre of this is mitochondrial dysfunction, secondary to hypoxia and systemic inflammation. This leads to a bioenergetic crisis, with decreased intramuscular adenosine tri-phosphate content and a reduction in the highly energy dependent process of protein synthesis. Numerous methods have been studied to try and reduce these effects, with only limited success. Trials investigating the use of increased calorie and protein administration have instead found a decrease in relative lean body mass, and a potential increase in morbidity and mortality. Ketone bodies have been proposed as alternative substrates for metabolism in critical illness, with promising results seen in animal models. They are currently being investigated in critical care patients in the Alternative Substrates in the Critically Ill Subjects trial. The evidence to date suggests that individualised feeding regimens may be key in the nutritional approach to critical illness. Consideration of individual patient factors will need to be combined with personalised protein content, total energy load received, and the timings of such feeds. This review covers mitochondrial dysfunction in critical illness, and how it contributes to muscle wasting and the resultant morbidity and mortality and the scientific basis of why current nutritional approaches to date have not been successful in negating this effect. These two factors underpin the need for consideration of alternative nutritional strategies in the critically ill patient. This article is protected by copyright. All rights reserved.
    Keywords:  Intensive care; Metabolism; Mitochondria; Muscle wasting; Nutrition
    DOI:  https://doi.org/10.1002/jpen.2190
  6. J Cell Physiol. 2021 Jun 08.
    A link between protein acetylation and mitochondrial dynamics under energy metabolism: A comprehensive overview.
    Huihui Gu, Kun Yang, Qiong Wu, Zhentong Shen, Xinjian Li, Chao Sun.
      Cells adjust mitochondrial morphologies to coordinate between the cellular demand for energy and the availability of resources. Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. Fission and fusion are dynamic and reversible processes that depend on the coordination of a number of proteins and are primarily regulated by posttranslational modifications. In the mitochondria, more than 20% of proteins are acetylated in proteomic surveys, partly involved in the dynamic regulation of mitochondrial fusion and fission. This article focuses on the molecular mechanism of the mitochondrial dynamics of fusion and fission, and summarizes the related mechanisms and targets of mitochondrial protein acetylation to regulate the mitochondrial dynamics of fusion and fission in energy metabolism.
    Keywords:  energy metabolism; mitochondrial dynamics; protein acetylation
    DOI:  https://doi.org/10.1002/jcp.30461
  7. Nat Commun. 2021 06 07. 12(1): 3379
    GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage.
    Lauren A Callender, Johannes Schroth, Elizabeth C Carroll, Conor Garrod-Ketchley, Lisa E L Romano, Eleanor Hendy, Audrey Kelly, Paul Lavender, Arne N Akbar, J Paul Chapple, Sian M Henson.
      GATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.
    DOI:  https://doi.org/10.1038/s41467-021-23715-7
  8. J Cell Sci. 2021 Jun 09. pii: jcs.258399. [Epub ahead of print]
    Maintenance of complex I and its super-complexes by NDUF-11 is essential for mitochondrial structure, function and health.
    Amber Knapp-Wilson, Gonçalo C Pereira, Emma Buzzard, Holly C Ford, Andrew Richardson, Robin A Corey, Chris Neal, Paul Verkade, Andrew P Halestrap, Vicki A M Gold, Patricia Kuwabara, Ian Collinson.
      Mitochondrial super-complexes form around a conserved core of monomeric complex I and dimeric complex III; wherein subunit NDUFA11, of the former, is conspicuously situated at the interface. We identified B0491.5 (NDUF-11) as the C. elegans homologue, of which animals homozygous for a CRISPR-Cas9 generated knockout allele arrested at the L2 development stage. Reducing (but not eliminating) expression by RNAi allowed development to adulthood, enabling characterisation of the consequences: destabilisation of complex I and its super-complexes, and perturbation of respiratory function. The loss of NADH-dehydrogenase activity is compensated by enhanced complex II activity, with the potential for detrimental ROS-production. Electron cryo-tomography highlight aberrant cristae morphology and inter-membrane-space widening and cristae-junctions. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development presumably arises due to its involvement in complex I/ super-complex maintenance. This highlights the importance of respiratory complex integrity for health and the potential of its perturbation for mitochondrial disease.
    Keywords:  Caenorhabditis elegans; Electron-transfer chain; Mitochondria; Mitochondrial ultrastructure; electron cryo-tomography; NDUF-11; Respirasome; Respiration; Super-complexes; Worm
    DOI:  https://doi.org/10.1242/jcs.258399
  9. J Cell Sci. 2021 Jun 10. pii: jcs.253443. [Epub ahead of print]
    The role of Mfn2 in the structure and function of ER-mitochondrial tethering in vivo.
    Song Han, Fanpeng Zhao, Jeffrey Hsia, Xiaopin Ma, Yi Liu, Sandy Torres, Hisashi Fujioka, Xiongwei Zhu.
      The mitochondria-ER contacts (MERCs) plays an essential role in multiple cell physiological process. While Mfn2 was the first protein implicated in the formation of MERCs, it is debated whether it acts as a tether or antagonizer, largely based on in vitro studies. To understand the role of Mfn2 in MERCs in vivo, we characterized ultrastructural and biochemical changes of MERCs in pyramidal neurons of hippocampus in Mfn2 conditional knockout (KO) mice and in Mfn2 overexpression (OE) mice and found Mfn2 ablation caused reduced close contacts while Mfn2 OE caused increased close contacts between ER and mitochondria in vivo. Functional studies on SH-SY5Y cells with Mfn2 KO or overexpression demonstrating similar biochemical changes found that mitochondrial calcium uptake along with IP3R3-Grp75 interaction was decreased in Mfn2 KO cells but increased in the Mfn2 OE cells. Lastly, we found Mfn2 KO decreased and Mfn2 OE increased the interaction between the ER-mitochondria tethering pair of VAPB-PTPIP51. In conclusion, our study supports the notion that Mfn2 plays a critical role in ER-mitochondrial tethering and the formation of close contacts in neuronal cells in vivo.
    Keywords:  ER-mitochondria tethering; Mfn2; Mitochondria-ER contact; Mitochondria-associated membrane; Mitochondrial calcium uptake; VAPB
    DOI:  https://doi.org/10.1242/jcs.253443
  10. Immunity. 2021 Jun 10. pii: S1074-7613(21)00210-7. [Epub ahead of print]
    Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.
    Hongxu Xian, Yuan Liu, Alexandra Rundberg Nilsson, Raphaella Gatchalian, Timothy R Crother, Warren G Tourtellotte, Yi Zhang, German R Aleman-Muench, Gavin Lewis, Weixuan Chen, Sarah Kang, Melissa Luevanos, Dorit Trudler, Stuart A Lipton, Pejman Soroosh, John Teijaro, Juan Carlos de la Torre, Moshe Arditi, Michael Karin, Elsa Sanchez-Lopez.
      Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
    Keywords:  ARDS; CMPK2; COVID-19; IL-1β; IL-6; NLRP3 inflammasome; SARS-CoV-2; inflammation; metformin; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.immuni.2021.05.004
  11. Appl Microbiol Biotechnol. 2021 Jun 09.
    Integrated signaling system under endoplasmic reticulum stress in eukaryotic microorganisms.
    Ting Cao, Binfeng Peng, Xiangping Zhou, Jialun Cai, Yun Tang, Jie Luo, Haitao Xie, Ji Zhang, Shuangquan Liu.
      The endoplasmic reticulum (ER) is a multifunctional organelle, which is crucial for correct folding and assembly of secretory and transmembrane proteins. Perturbations of ER function can cause ER stress. ER stress can activate the unfolded protein response (UPR) to cope with the accumulation of misfolded proteins and protein toxicity. UPR is a coordination system that regulates transcription and translation, leading to the recovery of ER homeostasis or cell death. However, cells have an integrated signaling system to cope with ER stress, which helps cells to restore and balance their ER function. The main components of this system are ER-associated degradation (ERAD), autophagy, hypoxia signaling, and mitochondrial biogenesis. If the balance cannot be restored, the imbalance will lead to cell death or apoptosis, or even to a series of diseases. In this review, a series of activities to restore the homeostasis of cells during ER stress are discussed. KEY POINTS: • Endoplasmic reticulum (ER) plays a key role in the biological process of cells. • Perturbations of ER function can cause ER stress, including the ER overload response (EOR), sterol-regulated cascade reaction, and the UPR. • Cells have an integrated signaling system (ERAD, autophagy, hypoxia signaling, and mitochondrial biogenesis) to cope with the adverse impact caused by ER stress.
    Keywords:  Autophagy; ER stress; ERAD; Endoplasmic reticulum; HIF-1; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1007/s00253-021-11380-1
  12. Ageing Res Rev. 2021 Jun 04. pii: S1568-1637(21)00125-2. [Epub ahead of print]70 101378
    Mitochondria: Their relevance during oocyte ageing.
    Jiska van der Reest, Gustavo Nardini Cecchino, Marcia C Haigis, Paweł Kordowitzki.
      The oocyte is recognised as the largest cell in mammalian species and other multicellular organisms. Mitochondria represent a high proportion of the cytoplasm in oocytes and mitochondrial architecture is different in oocytes than in somatic cells, characterised by a rounder appearance and fragmented network. Although the number of mitochondria per oocyte is higher than in any other mammalian cell, their number and activity decrease with advancing age. Mitochondria integrate numerous processes essential for cellular function, such as metabolic processes related to energy production, biosynthesis, and waste removal, as well as Ca2+ signalling and reactive oxygen species (ROS) homeostasis. Further, mitochondria are responsible for the cellular adaptation to different types of stressors such as oxidative stress or DNA damage. When these stressors outstrip the adaptive capacity of mitochondria to restore homeostasis, it leads to mitochondrial dysfunction. Decades of studies indicate that mitochondrial function is multifaceted, which is reflected in the oocyte, where mitochondria support numerous processes during oocyte maturation, fertilization, and early embryonic development. Dysregulation of mitochondrial processes has been consistently reported in ageing and age-related diseases. In this review, we describe the functions of mitochondria as bioenergetic powerhouses and signal transducers in oocytes, how dysfunction of mitochondrial processes contributes to reproductive ageing, and whether mitochondria could be targeted to promote oocyte rejuvenation.
    Keywords:  Metabolism; Mitochondria; Oocytes; Oxidative stress; Reproductive ageing
    DOI:  https://doi.org/10.1016/j.arr.2021.101378
  13. EMBO Rep. 2021 Jun 04. 22(6): e51323
    Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes.
    Hyun Ku Yeo, Tae Hyun Park, Hee Yeon Kim, Hyonchol Jang, Jueun Lee, Geum-Sook Hwang, Seong Eon Ryu, Si Hoon Park, Hyun Kyu Song, Hyun Seung Ban, Hye-Jin Yoon, Byung Il Lee.
      In eukaryotic cells, mitochondria are closely tethered to the endoplasmic reticulum (ER) at sites called mitochondria-associated ER membranes (MAMs). Ca2+ ion and phospholipid transfer occurs at MAMs to support diverse cellular functions. Unlike those in yeast, the protein complexes involved in phospholipid transfer at MAMs in humans have not been identified. Here, we determine the crystal structure of the tetratricopeptide repeat domain of PTPIP51 (PTPIP51_TPR), a mitochondrial protein that interacts with the ER-anchored VAPB protein at MAMs. The structure of PTPIP51_TPR shows an archetypal TPR fold, and an electron density map corresponding to an unidentified lipid-like molecule probably derived from the protein expression host is found in the structure. We reveal functions of PTPIP51 in phospholipid binding/transfer, particularly of phosphatidic acid, in vitro. Depletion of PTPIP51 in cells reduces the mitochondrial cardiolipin level. Additionally, we confirm that the PTPIP51-VAPB interaction is mediated by the FFAT-like motif of PTPIP51 and the MSP domain of VAPB. Our findings suggest that PTPIP51 is a phospholipid transfer protein with a MAM-tethering function.
    Keywords:  MAM; PTPIP51; endoplasmic reticulum; mitochondria; phospholipid
    DOI:  https://doi.org/10.15252/embr.202051323
  14. Adv Protein Chem Struct Biol. 2021 ;pii: S1876-1623(21)00025-0. [Epub ahead of print]126 307-343
    Apoptotic signals at the endoplasmic reticulum-mitochondria interface.
    Flavia Giamogante, Elena Poggio, Lucia Barazzuol, Alberto Covallero, Tito Calì.
      The maintenance of cellular homeostasis involves the participation of multiple organelles, such as the endoplasmic reticulum (ER) and mitochondria. Specifically, ER plays a key role in calcium (Ca2+) storage, lipid synthesis, protein folding, and assembly, while mitochondria are the "energy factories" and provide energy to drive intracellular processes. Hence, alteration in ER or mitochondrial homeostasis has detrimental effects on cell survival, being linked to the triggering of apoptosis, a programmed form of cell death. Besides, ER stress conditions affect mitochondria functionality and vice-versa, as ER and mitochondria communicate via mitochondria-associated ER membranes (MAMs) to carry out a number of fundamental cellular functions. It is not surprising, thus, that also MAMs perturbations are involved in the regulation of apoptosis. This chapter intends to accurately discuss the involvement of MAMs in apoptosis, highlighting their crucial role in controlling this delicate cellular process.
    Keywords:  Apoptosis; Bioenergetics; Calcium signaling; ER-mitochondria contact sites; MAMs; Organelle tethering
    DOI:  https://doi.org/10.1016/bs.apcsb.2021.02.007
  15. PLoS Comput Biol. 2021 Jun 09. 17(6): e1009073
    Optimizing mitochondrial maintenance in extended neuronal projections.
    Anamika Agrawal, Elena F Koslover.
      Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mitochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, a key aspect underlying many neurodegenerative disorders.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009073
  16. Cell Death Dis. 2021 Jun 05. 12(6): 579
    Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages.
    Andreas Lindhorst, Nora Raulien, Peter Wieghofer, Jens Eilers, Fabio M V Rossi, Ingo Bechmann, Martin Gericke.
      A chronic low-grade inflammation within adipose tissue (AT) seems to be the link between obesity and some of its associated diseases. One hallmark of this AT inflammation is the accumulation of AT macrophages (ATMs) around dead or dying adipocytes, forming so-called crown-like structures (CLS). To investigate the dynamics of CLS and their direct impact on the activation state of ATMs, we established a laser injury model to deplete individual adipocytes in living AT from double reporter mice (GFP-labeled ATMs and tdTomato-labeled adipocytes). Hence, we were able to detect early ATM-adipocyte interactions by live imaging and to determine a precise timeline for CLS formation after adipocyte death. Further, our data indicate metabolic activation and increased lipid metabolism in ATMs upon forming CLS. Most importantly, adipocyte death, even in lean animals under homeostatic conditions, leads to a locally confined inflammation, which is in sharp contrast to other tissues. We identified cell size as cause for the described pro-inflammatory response, as the size of adipocytes is above a critical threshold size for efferocytosis, a process for anti-inflammatory removal of dead cells during tissue homeostasis. Finally, experiments on parabiotic mice verified that adipocyte death leads to a pro-inflammatory response of resident ATMs in vivo, without significant recruitment of blood monocytes. Our data indicate that adipocyte death triggers a unique degradation process and locally induces a metabolically activated ATM phenotype that is globally observed with obesity.
    DOI:  https://doi.org/10.1038/s41419-021-03872-9
  17. EMBO J. 2021 Jun 07. e107826
    SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation.
    Lucy G Thorne, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Matthew V X Whelan, Jane Turner, Mahdad Noursadeghi, Clare Jolly, Greg J Towers.
      SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through activation of cytoplasmic RNA-sensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing, or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19.
    Keywords:  RNA sensing; SARS-CoV-2; epithelial; inflammation; macrophage
    DOI:  https://doi.org/10.15252/embj.2021107826
  18. Physiol Genomics. 2021 06 07.
    Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents.
    Peter Celec, Ľubica Janovičová, Radana Gurecká, Ivana Koborová, Roman Gardlík, Katarina Sebekova.
      Obesity is associated with chronic low-grade inflammation that eventually leads to metabolic complications. Extracellular DNA (ecDNA) is a damage-associated molecular pattern. Extracellular mitochondrial DNA can activate innate immunity. We hypothesized that ecDNA, especially of mitochondrial origin could be associated with components of the metabolic syndrome in young healthy probands. In a cross-sectional study healthy adolescents (n=1249) provided blood samples. Anthropometric data, blood pressure and blood counts were assessed. In addition, biochemical analysis of sera or plasma was conducted including the quantification of advanced oxidation protein products (AOPP) as a marker of oxidative stress induced by neutrophil or monocyte activation. Plasma ecDNA was isolated and measured using fluorometry. Nuclear and mitochondrial DNA were quantified using real time PCR. Males had higher total plasma ecDNA (15 (11-21) vs 11 (8-17) ng/ml; median (IQR)), nuclear (1760 (956-3273) vs 1153 (600-2292) GE/ml) and mitochondrial DNA (37181 (14836-90896) vs 30089 (12587-72286) GE/ml). EcDNA correlated positively with the continuous metabolic syndrome score (r= 0.158 for males and r= 0.134 for females). Stronger correlations were found between ecDNA of mitochondrial origin and AOPP (r= 0.202 and 0.186 for males and females respectively). Multivariate regression analysis revealed associations of nuclear DNA with leukocyte and erythrocyte counts. The results of this study on healthy adolescents show that circulating ecDNA is associated with the risk of metabolic syndrome, not with obesity per se. The association between mitochondrial ecDNA and AOPP requires further attention as it supports a potential role of mitochondria-induced sterile inflammation in the pathogenesis of the metabolic syndrome.
    Keywords:  cell-free DNA; metabolic syndrome; microinflammation; obesity; observational study
    DOI:  https://doi.org/10.1152/physiolgenomics.00029.2021
  19. Mol Cell. 2021 Jun 02. pii: S1097-2765(21)00400-7. [Epub ahead of print]
    Bacterial RF3 senses chaperone function in co-translational folding.
    Liang Zhao, Marie-Pierre Castanié-Cornet, Sneha Kumar, Pierre Genevaux, Manajit Hayer-Hartl, F Ulrich Hartl.
      Molecular chaperones assist with protein folding by interacting with nascent polypeptide chains (NCs) during translation. Whether the ribosome can sense chaperone defects and, in response, abort translation of misfolding NCs has not yet been explored. Here we used quantitative proteomics to investigate the ribosome-associated chaperone network in E. coli and the consequences of its dysfunction. Trigger factor and the DnaK (Hsp70) system are the major NC-binding chaperones. HtpG (Hsp90), GroEL, and ClpB contribute increasingly when DnaK is deficient. Surprisingly, misfolding because of defects in co-translational chaperone function or amino acid analog incorporation results in recruitment of the non-canonical release factor RF3. RF3 recognizes aberrant NCs and then moves to the peptidyltransferase site to cooperate with RF2 in mediating chain termination, facilitating clearance by degradation. This function of RF3 reduces the accumulation of misfolded proteins and is critical for proteostasis maintenance and cell survival under conditions of limited chaperone availability.
    Keywords:  ClpB; DnaJ; DnaK; GroEL; GrpE; Hsp70; Hsp90; HtpG; PrfC (RF3); co-translational protein folding; molecular chaperones; proteomics; translation termination; trigger factor
    DOI:  https://doi.org/10.1016/j.molcel.2021.05.016
  20. EMBO J. 2021 Jun 08. e106438
    An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial membrane.
    Fujiao Lv, Fei Qi, Zhi Zhang, Maorong Wen, Justin Kale, Alessandro Piai, Lingyu Du, Shuqing Wang, Liujuan Zhou, Yaqing Yang, Bin Wu, Zhijun Liu, Juan Del Rosario, Justin Pogmore, James J Chou, David W Andrews, Jialing Lin, Bo OuYang.
      Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. This might involve their embedding in the cytosolic leaflet of the lipid bilayer, thus generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, Bax proteins might comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determined a high-resolution structure of the Bax core region, revealing a dimer with the nonpolar surface covering the lipid bilayer edge and the polar surface exposed to water. The dimer tilts from the bilayer normal, not only maximizing nonpolar interactions with lipid tails but also creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both types of protein-lipid interactions in Bax pore assembly and core dimer configuration. Therefore, the Bax core dimer forms part of the proteolipid pore wall to permeabilize mitochondria.
    Keywords:  NMR structure; bax core dimer; functional mutagenesis; membrane lipid bilayer; pore formation
    DOI:  https://doi.org/10.15252/embj.2020106438
  21. Nat Rev Immunol. 2021 Jun 07.
    The role of T cells in age-related diseases.
    Elisa Carrasco, Manuel M Gómez de Las Heras, Enrique Gabandé-Rodríguez, Gabriela Desdín-Micó, Juan Francisco Aranda, Maria Mittelbrunn.
      Age-related T cell dysfunction can lead to failure of immune tolerance mechanisms, resulting in aberrant T cell-driven cytokine and cytotoxic responses that ultimately cause tissue damage. In this Review, we discuss the role of T cells in the onset and progression of age-associated conditions, focusing on cardiovascular disorders, metabolic dysfunction, neuroinflammation and defective tissue repair and regeneration. We present different mechanisms by which T cells contribute to inflammageing and might act as modulators of age-associated diseases, including through enhanced pro-inflammatory and cytotoxic activity, defective clearance of senescent cells or regulation of the gut microbiota. Finally, we propose that 'resetting' immune system tolerance or targeting pathogenic T cells could open up new therapeutic opportunities to boost resilience to age-related diseases.
    DOI:  https://doi.org/10.1038/s41577-021-00557-4
  22. J Cell Sci. 2021 Jun 01. pii: jcs256230. [Epub ahead of print]134(11):
    Interferon regulatory factor 7 impairs cellular metabolism in aging adipose-derived stromal cells.
    Alice Nodari, Ilaria Scambi, Daniele Peroni, Elisa Calabria, Donatella Benati, Silvia Mannucci, Marcello Manfredi, Andrea Frontini, Silvia Visonà, Andrea Bozzato, Andrea Sbarbati, Federico Schena, Emilio Marengo, Mauro Krampera, Mirco Galiè.
      Dysregulated immunity and widespread metabolic dysfunctions are the most relevant hallmarks of the passing of time over the course of adult life, and their combination at midlife is strongly related to increased vulnerability to diseases; however, the causal connection between them remains largely unclear. By combining multi-omics and functional analyses of adipose-derived stromal cells established from young (1 month) and midlife (12 months) mice, we show that an increase in expression of interferon regulatory factor 7 (IRF7) during adult life drives major metabolic changes, which include impaired mitochondrial function, altered amino acid biogenesis and reduced expression of genes involved in branched-chain amino acid (BCAA) degradation. Our results draw a new paradigm of aging as the 'sterile' activation of a cell-autonomous pathway of self-defense and identify a crucial mediator of this pathway, IRF7, as driver of metabolic dysfunction with age.
    Keywords:  Aging; Branched-chain amino acid degradation; Cellular metabolism; IFN signaling; Interferon regulatory factor 7; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.256230
  23. Mitochondrion. 2021 Jun 05. pii: S1567-7249(21)00078-7. [Epub ahead of print]
    A hitchhiker's guide to mitochondrial quantification.
    Irene Mgm Hemel, Bob Ph Engelen, Nicole Luber, Mike Gerards.
      The variety of available mitochondrial quantification tools makes it difficult to select the most reliable and accurate quantification tool. Here, we performed elaborate analyses on five open source ImageJ tools. Excessive clustering of mitochondrial structures was observed in four tools, caused by the global thresholding applied by these tools. The Mitochondrial Analyzer, which uses adaptive thresholding, outperformed the other examined tools, with accurate structural segregation and identification. Additionally, we showed that the Mitochondrial Analyzer successfully identifies mitochondrial morphology differences. Based on the observed performance, we consider the Mitochondrial Analyzer the best open source tool for mitochondrial network morphology quantification.
    Keywords:  Image analysis; ImageJ; Mitochondria; Mitochondrial Dynamics; Mitochondrial quantification
    DOI:  https://doi.org/10.1016/j.mito.2021.06.005
  24. J Biol Chem. 2021 Jun 04. pii: S0021-9258(21)00656-6. [Epub ahead of print] 100856
    Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection.
    Qingtang Shen, Yifan E Wang, Alexander F Palazzo.
      The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1,000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signalling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.
    Keywords:  IRF3; NF-κB; Nuclear pore proteins; STATs; innate immune responses; karyopherins; nucleocytoplasmic trafficking; viral immune evasion
    DOI:  https://doi.org/10.1016/j.jbc.2021.100856
  25. J Neurosci. 2021 Jun 08. pii: JN-RM-2159-20. [Epub ahead of print]
    Early inflammation dysregulates neuronal circuit formation in vivo via upregulation of IL-1β.
    Cynthia M Solek, Nasr A I Farooqi, Niklas Brake, Philip Kesner, Anne Schohl, Jack P Antel, Edward S Ruthazer.
      Neuro-immune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyper-dynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish we showed that these morphological changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1β (IL-1β) is upregulated by the inflammatory insult, and that down-regulation of IL-1β abrogated the effects of inflammation on axonal dynamics and growth. Moreover, baseline branching of the RGC arbors in IL-1β morphant animals was significantly different from that in control larvae, and their performance in a predation assay was impaired, indicating a role for this cytokine in normal neuronal development. This work establishes a simple and powerful non-mammalian model of developmental immune activation and demonstrates a role for IL-1β in mediating the pathological effects of inflammation on neuronal circuit development.SIGNIFICANCE STATEMENTMaternal immune activation (MIA) can increase the risk of neurodevelopmental disorders in offspring, however the mechanisms involved are not fully understood. Using a non-mammalian vertebrate model of developmental immune activation, we show that even brief activation of inflammatory pathways has immediate and long-term effects on the arborization of axons, and that these morphological changes have functional and behavioral consequences. Finally, we show that the pro-inflammatory cytokine IL-1β plays an essential role in both the effects of inflammation on circuit formation and normal axonal development. Our data add to a growing body of evidence supporting epidemiological studies linking immune activation to neurodevelopmental disorders, and help shed light on the molecular and cellular processes that contribute to the etiology of these disorders.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2159-20.2021
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