bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2021–08–08
seventeen papers selected by
Avinash N. Mukkala, University of Toronto
  1. Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
  2. Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
  3. Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
  4. BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
  5. A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
  6. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.
  7. The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection.
  8. Mff oligomerization is required for Drp1 activation and synergy with actin filaments during mitochondrial division.
  9. Mitotherapy: Unraveling a Promising Treatment for Disorders of the Central Nervous System and Other Systemic Conditions.
  10. Hypothermia Promotes Mitochondrial Elongation In Cardiac Cells Via Inhibition Of Drp1.
  11. Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.
  12. The Roles of Assembly Factors in Mammalian Mitoribosome Biogenesis.
  13. Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
  14. Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19.
  15. FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply.
  16. Alterations in mitochondrial morphology as a key driver of immunity and host defence.
  17. Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
  1. Sci Adv. 2021 Aug;pii: eabf6580. [Epub ahead of print]7(32):
    Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.
    Huihui Li, Zak Doric, Amandine Berthet, Danielle M Jorgens, Mai K Nguyen, Ivy Hsieh, Julia Margulis, Rebecca Fang, Jayanta Debnath, Hiromi Sesaki, Steve Finkbeiner, Eric Huang, Ken Nakamura.
      Altered mitochondrial quality control and dynamics may contribute to neurodegenerative diseases, including Parkinson's disease, but we understand little about these processes in neurons. We combined time-lapse microscopy and correlative light and electron microscopy to track individual mitochondria in neurons lacking the fission-promoting protein dynamin-related protein 1 (Drp1) and delineate the kinetics of PINK1-dependent pathways of mitochondrial quality control. Depolarized mitochondria recruit Parkin to the outer mitochondrial membrane, triggering autophagosome formation, rapid lysosomal fusion, and Parkin redistribution. Unexpectedly, these mitolysosomes are dynamic and persist for hours. Some are engulfed by healthy mitochondria, and others are deacidified before bursting. In other cases, Parkin is directly recruited to the matrix of polarized mitochondria. Loss of PINK1 blocks Parkin recruitment, causes LC3 accumulation within mitochondria, and exacerbates Drp1KO toxicity to dopamine neurons. These results define a distinct neuronal mitochondrial life cycle, revealing potential mechanisms of mitochondrial recycling and signaling relevant to neurodegeneration.
    DOI:  https://doi.org/10.1126/sciadv.abf6580
  2. Development. 2021 Aug 06. pii: dev.199686. [Epub ahead of print]
    Fis1 ablation in the male germline disrupts mitochondrial morphology and mitophagy, and arrests spermatid maturation.
    Grigor Varuzhanyan, Mark S Ladinsky, Shun-Ichi Yamashita, Manabu Abe, Kenji Sakimura, Tomotake Kanki, David C Chan.
      Male germline development involves choreographed changes to mitochondrial number, morphology, and organization. Mitochondrial reorganization during spermatogenesis was recently shown to require mitochondrial fusion and fission. Mitophagy, the autophagic degradation of mitochondria, is another mechanism for controlling mitochondrial number and physiology, but its role during spermatogenesis is largely unknown. During post-meiotic spermatid development, restructuring of the mitochondrial network results in packing of mitochondria into a tight array in the sperm midpiece to fuel motility. Here, we show that disruption of mouse Fis1 in the male germline results in early spermatid arrest that is associated with increased mitochondrial content. Mutant spermatids coalesce into multinucleated giant cells (GCs) that accumulate mitochondria of aberrant ultrastructure and numerous mitophagic and autophagic intermediates, suggesting a defect in mitophagy. We conclude that Fis1 regulates mitochondrial morphology and turnover to promote spermatid maturation.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitophagy; Spermatid; Spermatogenesis
    DOI:  https://doi.org/10.1242/dev.199686
  3. Biochim Biophys Acta Gen Subj. 2021 Jul 28. pii: S0304-4165(21)00131-8. [Epub ahead of print]1865(10): 129972
    Molecular functions of autophagy adaptors upon ubiquitin-driven mitophagy.
    Koji Yamano, Waka Kojima.
       BACKGROUND: Perturbations in organellar health can lead to an accumulation of unwanted and/or damaged organelles that are toxic to the cell and which can contribute to the onset of neurodegenerative diseases such as Parkinson's disease. Mitochondrial health is particularly critical given the indispensable role the organelle has not only in adenosine triphosphate production but also other metabolic processes. Byproducts of oxidative respiration, such as reactive oxygen species, however, can negatively impact mitochondrial fitness. Consequently, selective degradation of damaged mitochondria, which occurs via a specific autophagic process termed mitophagy, is essential for normal cell maintenance.
    SCOPE OF REVIEW: Recent accumulating evidence has shown that autophagy adaptors (also referred to as autophagy receptors) play critical roles in connecting ubiquitinated mitochondria with the autophagic machinery of the autophagy-lysosome pathway that is required for degradation. In this review, we focus on our current understanding of the autophagy adaptor mechanisms underlying PINK1/Parkin-driven mitophagy.
    MAJOR CONCLUSIONS: Although autophagy adaptors are canonically defined as proteins that possess ubiquitin-binding domains and ATG8s-binding motifs, the recent identification of novel binding partners has contributed to the development of a more sophisticated model for how autophagy adaptors contribute to the molecular hub that organizes autophagic cargo-degradation.
    GENERAL SIGNIFICANCE: Although mitophagy is recognized as one of the selective autophagy pathways that removes dysfunctional mitochondria, a more nuanced understanding of the interactions connecting autophagy adaptors and their associated proteins is needed to gain deeper insights into the fundamental biological processes underlying human diseases, including neurodegenerative disorders. This review is part of a Special Issue entitled Mitophagy.
    DOI:  https://doi.org/10.1016/j.bbagen.2021.129972
  4. Cells. 2021 Jul 20. pii: 1839. [Epub ahead of print]10(7):
    BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation.
    Deokha Kim, Jinsoo Song, Eun-Jung Jin.
      Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3' untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases.
    Keywords:  BNIP3; PGC1A; autophagy; miR-126-5p; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.3390/cells10071839
  5. Liver Res. 2021 Mar;5(1): 16-20
    A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver.
    Xiaowen Ma, Wen-Xing Ding.
       Background and aim: Mitophagy is a lysosomal degradation pathway that selectively removes damaged, aged and dysfunctional mitochondria. Recent advances in understanding mitophagy highlight its importance in various physiological and pathological conditions including liver diseases. However, reliable quantitative assays to monitor mitophagy in cultured cells and in tissues are still scarce.
    Methods: We describe a detailed protocol for monitoring mitophagy in primary cultured hepatocytes and mouse livers using cytochrome C oxidase subunit 8 (Cox8)-enhanced green fluorescent protein (EGFP)-mCherry, a dual color fluorescence based-imaging method.
    Results: Mitochondria are visualized in yellow fluorescence due to the merged EGFP and mCherry signal. In contrast, autolysosome enclosed mitochondria are shown as red puncta due to quenching of EGFP green fluorescence in acidic compartments. Quantifying the number of red-only puncta in each cell can obtain a quantitative measure for mitophagy.
    Conclusions: Cox8-EGFP-mCherry assay can specifically target to mitochondria and be used to monitor mitophagy in vitro and in vivo.
    Keywords:  Autophagy; Cox8-EGFP-mCherry; Fluorescence microscopy; Lysosome; Mitochondria
    DOI:  https://doi.org/10.1016/j.livres.2020.12.002
  6. Int J Mol Sci. 2021 Aug 02. pii: 8312. [Epub ahead of print]22(15):
    Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer.
    Daniela Valenti, Rosa Anna Vacca, Loredana Moro, Anna Atlante.
      Mitochondria are complex intracellular organelles traditionally identified as the powerhouses of eukaryotic cells due to their central role in bioenergetic metabolism. In recent decades, the growing interest in mitochondria research has revealed that these multifunctional organelles are more than just the cell powerhouses, playing many other key roles as signaling platforms that regulate cell metabolism, proliferation, death and immunological response. As key regulators, mitochondria, when dysfunctional, are involved in the pathogenesis of a wide range of metabolic, neurodegenerative, immune and neoplastic disorders. Far more recently, mitochondria attracted renewed attention from the scientific community for their ability of intercellular translocation that can involve whole mitochondria, mitochondrial genome or other mitochondrial components. The intercellular transport of mitochondria, defined as horizontal mitochondrial transfer, can occur in mammalian cells both in vitro and in vivo, and in physiological and pathological conditions. Mitochondrial transfer can provide an exogenous mitochondrial source, replenishing dysfunctional mitochondria, thereby improving mitochondrial faults or, as in in the case of tumor cells, changing their functional skills and response to chemotherapy. In this review, we will provide an overview of the state of the art of the up-to-date knowledge on intercellular trafficking of mitochondria by discussing its biological relevance, mode and mechanisms underlying the process and its involvement in different pathophysiological contexts, highlighting its therapeutic potential for diseases with mitochondrial dysfunction primarily involved in their pathogenesis.
    Keywords:  bioenergetics; cancer; ccf-mtDNA; extracellular mitochondria; extracellular mitovesicles; immune-metabolic regulation; intercellular mitochondria trafficking; mitochondria; mitochondrial transplantation; neurodegenerative diseases; neurodevelopmental disorders; oxidative phosphorylation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms22158312
  7. Proc Natl Acad Sci U S A. 2021 Aug 10. pii: e2101675118. [Epub ahead of print]118(32):
    The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection.
    Cora N Betsinger, Connor S R Jankowski, William A Hofstadter, Joel D Federspiel, Clayton J Otter, Pierre M Jean Beltran, Ileana M Cristea.
      Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.
    Keywords:  HCMV; metabolism; mitochondria; pUL13; proteomics
    DOI:  https://doi.org/10.1073/pnas.2101675118
  8. Mol Biol Cell. 2021 Aug 04. mbcE21040224
    Mff oligomerization is required for Drp1 activation and synergy with actin filaments during mitochondrial division.
    Ao Liu, Frieda Kage, Henry N Higgs.
      Mitochondrial division is an important cellular process in both normal and pathological conditions. The dynamin GTPase Drp1 is a central mitochondrial division protein, driving constriction of the outer mitochondrial membrane. In mammals, the outer mitochondrial membrane protein Mff is a key receptor for recruiting Drp1 from the cytosol to the mitochondrion. Actin filaments are also important in Drp1 recruitment and activation. The manner in which Mff and actin work together in Drp1 activation is unknown. Here, we show that Mff is an oligomer (most likely a trimer) that dynamically associates and disassociates through its C-terminal coiled-coil, with a Kd in the range of 10 µM. Dynamic Mff oligomerization is required for Drp1 activation. While not binding Mff directly, actin filaments enhance Mff-mediated Drp1 activation by lowering the effective Mff concentration 10-fold. Total internal reflection microscopy assays using purified proteins show that Mff interacts with Drp1 on actin filaments in a manner dependent on Mff oligomerization. In U2OS cells, oligomerization-defective Mff does not effectively rescue three defects in Mff knock-out cells: mitochondrial division, mitochondrial Drp1 recruitment, and peroxisome division. The ability of Mff to assemble into puncta on mitochondria depends on its oligomerization, as well as on actin filaments and Drp1.
    DOI:  https://doi.org/10.1091/mbc.E21-04-0224
  9. Cells. 2021 Jul 20. pii: 1827. [Epub ahead of print]10(7):
    Mitotherapy: Unraveling a Promising Treatment for Disorders of the Central Nervous System and Other Systemic Conditions.
    Gabriel Nascimento-Dos-Santos, Eduardo de-Souza-Ferreira, Rafael Linden, Antonio Galina, Hilda Petrs-Silva.
      Mitochondria are key players of aerobic respiration and the production of adenosine triphosphate and constitute the energetic core of eukaryotic cells. Furthermore, cells rely upon mitochondria homeostasis, the disruption of which is reported in pathological processes such as liver hepatotoxicity, cancer, muscular dystrophy, chronic inflammation, as well as in neurological conditions including Alzheimer's disease, schizophrenia, depression, ischemia and glaucoma. In addition to the well-known spontaneous cell-to-cell transfer of mitochondria, a therapeutic potential of the transplant of isolated, metabolically active mitochondria has been demonstrated in several in vitro and in vivo experimental models of disease. This review explores the striking outcomes achieved by mitotherapy thus far, and the most relevant underlying data regarding isolated mitochondria transplantation, including mechanisms of mitochondria intake, the balance between administration and therapy effectiveness, the relevance of mitochondrial source and purity and the mechanisms by which mitotherapy is gaining ground as a promising therapeutic approach.
    Keywords:  central nervous system; mitochondria; mitotherapy; neurodegeneration; therapy
    DOI:  https://doi.org/10.3390/cells10071827
  10. Cryobiology. 2021 Jul 28. pii: S0011-2240(21)00137-1. [Epub ahead of print]
    Hypothermia Promotes Mitochondrial Elongation In Cardiac Cells Via Inhibition Of Drp1.
    David Taylor, Juliana Germano, Yang Song, Hanane Hadj-Moussa, Stefanie Marek-Iannucci, Raeesa Dhanji, Jon Sin, Lawrence S C Czer, Kenneth B Storey, Roberta A Gottlieb.
      Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32°C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32°C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.
    Keywords:  Drp1; Mitochondria; TRPV1; hypothermia; mitochondrial fission
    DOI:  https://doi.org/10.1016/j.cryobiol.2021.07.013
  11. Mol Cell. 2021 Jul 27. pii: S1097-2765(21)00583-9. [Epub ahead of print]
    Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER.
    David M Booth, Péter Várnai, Suresh K Joseph, György Hajnóczky.
      The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.
    Keywords:  Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain
    DOI:  https://doi.org/10.1016/j.molcel.2021.07.014
  12. Mitochondrion. 2021 Jul 30. pii: S1567-7249(21)00101-X. [Epub ahead of print]
    The Roles of Assembly Factors in Mammalian Mitoribosome Biogenesis.
    Taru Hilander, Christopher B Jackson, Marius Robciuc, Tanzeela Bashir, Hongxia Zhao.
      As ancient bacterial endosymbionts of eukaryotic cells, mitochondria have retained their own circular DNA as well as protein translation system including mitochondrial ribosomes (mitoribosomes). In recent years, methodological advancements in cryoelectron microscopy and mass spectrometry have revealed the extent of the evolutionary divergence of mitoribosomes from their bacterial ancestors and their adaptation to the synthesis of 13 mitochondrial DNA encoded oxidative phosphorylation complex subunits. In addition to the structural data, the first assembly pathway maps of mitoribosomes have started to emerge and concomitantly also the assembly factors involved in this process to achieve fully translational competent particles. These transiently associated factors assist in the intricate assembly process of mitoribosomes by enhancing protein incorporation, ribosomal RNA folding and modification, and by blocking premature or non-native protein binding, for example. This review focuses on summarizing the current understanding of the known mammalian mitoribosome assembly factors and discussing their possible roles in the assembly of small or large mitoribosomal subunits.
    Keywords:  mitochondrial translation; mitoribosome assembly factors; mitoribosome biogenesis
    DOI:  https://doi.org/10.1016/j.mito.2021.07.008
  13. Exp Gerontol. 2021 Aug 03. pii: S0531-5565(21)00290-4. [Epub ahead of print] 111508
    Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
    Anna Picca, Riccardo Calvani, Hélio José Coelho-Júnior, Emanuele Marzetti.
      Cardiovascular disease is highly prevalent among older adults and poses a huge burden on morbidity, disability, and mortality. The age-related increased vulnerability of the cardiovascular system towards stressors is as a pathophysiological trait of cardiovascular disease. This has been associated with a progressive deterioration of blood vessels and decline in heart function during aging. Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondrial metabolism is crucial to this purpose. Dysmorphic, inefficient, and oxidant-producing mitochondria have been identified in aged cardiomyocytes in the setting of cardiac structural and functional alterations. These aberrant organelles are thought to arise from inefficient mitochondrial quality control, which has therefore been place in the spotlight as a relevant mechanism of cardiac aging. As a result of alterations in mitochondrial quality control and imbalanced oxidant defense, mitochondrial damage accumulates and contributes to cardiac frailty. Herein, we discuss the contribution of defective mitochondrial quality control pathways to cardiac frailty. Emerging findings pointing towards the exploitation of these pathways as therapeutic targets against cardiac aging and cardiovascular disease will also be illustrated.
    Keywords:  Autophagy; Cardioprotection; Extracellular vesicles; Mitochondrial derived vesicles; Mitochondrial quality control; Therapeutics
    DOI:  https://doi.org/10.1016/j.exger.2021.111508
  14. Int J Mol Sci. 2021 Jul 30. pii: 8180. [Epub ahead of print]22(15):
    Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19.
    Shailendra Pratap Singh, Salomon Amar, Pinky Gehlot, Sanjib K Patra, Navjot Kanwar, Abhinav Kanwal.
      Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.
    Keywords:  COVID-19; SARS-COV2; autophagy; mitochondria; potential targets; viral infections
    DOI:  https://doi.org/10.3390/ijms22158180
  15. J Cell Biol. 2021 Oct 04. pii: e201912077. [Epub ahead of print]220(10):
    FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply.
    Himanish Basu, Gulcin Pekkurnaz, Jill Falk, Wei Wei, Morven Chin, Judith Steen, Thomas L Schwarz.
      Mitochondrial movement and distribution are fundamental to their function. Here we report a mechanism that regulates mitochondrial movement by anchoring mitochondria to the F-actin cytoskeleton. This mechanism is activated by an increase in glucose influx and the consequent O-GlcNAcylation of TRAK (Milton), a component of the mitochondrial motor-adaptor complex. The protein four and a half LIM domains protein 2 (FHL2) serves as the anchor. FHL2 associates with O-GlcNAcylated TRAK and is both necessary and sufficient to drive the accumulation of F-actin around mitochondria and to arrest mitochondrial movement by anchoring to F-actin. Disruption of F-actin restores mitochondrial movement that had been arrested by either TRAK O-GlcNAcylation or forced direction of FHL2 to mitochondria. This pathway for mitochondrial immobilization is present in both neurons and non-neuronal cells and can thereby adapt mitochondrial dynamics to changes in glucose availability.
    DOI:  https://doi.org/10.1083/jcb.201912077
  16. EMBO Rep. 2021 Aug 02. e53086
    Alterations in mitochondrial morphology as a key driver of immunity and host defence.
    Mariana P Cervantes-Silva, Shannon L Cox, Annie M Curtis.
      Mitochondria are dynamic organelles whose architecture changes depending on the cell's energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.
    Keywords:  bacteria; immune response; mitochondrial dynamics; therapy; virus
    DOI:  https://doi.org/10.15252/embr.202153086
  17. Elife. 2021 Aug 03. pii: e67604. [Epub ahead of print]10
    Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.
    Francois Singh, Alan R Prescott, Philippa Rosewell, Graeme Ball, Alastair D Reith, Ian G Ganley.
      Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
    Keywords:  LRRK2; Mitophagy; cell biology; kinase inhibitor; mito-QC; mouse; neuroscience; parkinson's disease
    DOI:  https://doi.org/10.7554/eLife.67604
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