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https://www.readbyqxmd.com/read/29166700/dlp1-dependent-mitochondrial-fragmentation-and-redistribution-mediate-prion-associated-mitochondrial-dysfunction-and-neuronal-death
#1
Chaosi Li, Di Wang, Wei Wu, Wei Yang, Syed Zahid Ali Shah, Ying Zhao, Yuhan Duan, Lu Wang, Xiangmei Zhou, Deming Zhao, Lifeng Yang
Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin-like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP(106-126) in vitro as well as in prion strain-infected hamster brain in vivo...
November 22, 2017: Aging Cell
https://www.readbyqxmd.com/read/29163190/sr-bi-mediated-transcytosis-of-hdl-in-brain-microvascular-endothelial-cells-is-independent-of-caveolin-clathrin-and-pdzk1
#2
Karen Y Fung, Changsen Wang, Steffen Nyegaard, Bryan Heit, Gregory D Fairn, Warren L Lee
The vascular endothelium supplying the brain exhibits very low paracellular and transcellular permeability and is a major constituent of the blood-brain barrier. High-density lipoprotein (HDL) crosses the blood-brain barrier by transcytosis, but technical limitations have made it difficult to elucidate its regulation. Using a combination of spinning-disc confocal and total internal reflection fluorescence microscopy, we examined the uptake and transcytosis of HDL by human primary brain microvascular endothelial cell monolayers...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29158231/receptor-mediated-drp1-oligomerization-on-endoplasmic-reticulum
#3
Wei-Ke Ji, Rajarshi Chakrabarti, Xintao Fan, Lori Schoenfeld, Stefan Strack, Henry N Higgs
Drp1 is a dynamin guanosine triphosphatase important for mitochondrial and peroxisomal division. Drp1 oligomerization and mitochondrial recruitment are regulated by multiple factors, including interaction with mitochondrial receptors such as Mff, MiD49, MiD51, and Fis. In addition, both endoplasmic reticulum (ER) and actin filaments play positive roles in mitochondrial division, but mechanisms for their roles are poorly defined. Here, we find that a population of Drp1 oligomers is associated with ER in mammalian cells and is distinct from mitochondrial or peroxisomal Drp1 populations...
November 20, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29152606/ethanol-induced-steatosis-involves-impairment-of-lipophagy-associated-with-reduced-dynamin2-activity
#4
Karuna Rasineni, Terrence M Donohue, Paul G Thomes, Li Yang, Dean J Tuma, Mark A McNiven, Carol A Casey
Background: Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down-regulating Dynamin 2 (Dyn2), a protein that facilitates lysosome re-formation, contributing to hepatocellular steatosis. Methods: Primary hepatocytes were isolated from male Wistar rats fed Lieber-DeCarli control or EtOH liquid diets for 6-8 wk. Hepatocytes were incubated in complete medium (fed) or nutrient-free medium (fasting) with or without the Dyn2 inhibitor Dynasore or the Src inhibitor SU6656...
August 2017: Hepatol Commun
https://www.readbyqxmd.com/read/29150487/dynamin-inhibitors-block-mtorc1-activation-by-amino-acids-independently-of-dynamin
#5
Persaud Avinash, Cormerais Yann, Pouyssegur Jacques, Rotin Daniela
mTORC1 plays a critical role in protein synthesis and cell proliferation and growth. It is activated by growth factors and amino acids, including essential amino acid (EAA), such as Leu; Leu enters cells via the Leu transporter LAT1-4F2hc and potentially via endocytosis. Here we investigated the contribution of the different routes of Leu entry into cells to mTORC1 activation using pharmacological inhibitors and cells that lack LAT1 or dynamin1/2/3. Our results show that LAT1 is the major route of Leu entry into cells and mTORC1 activation (∼70%), while dynamin-dependent endocytosis and macropinocytosis contribute minimally to both (5-15%)...
November 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29142129/entry-of-human-coronavirus-nl63-to-the-cell
#6
Aleksandra Milewska, Paulina Nowak, Katarzyna Owczarek, Artur Szczepanski, Miroslaw Zarebski, Agnieszka Hoang-Bujnowicz, Krzysztof Berniak, Jacek Wojarski, Slawomir Zeglen, Zbigniew Baster, Zenon Rajfur, Krzysztof Pyrc
First steps of human coronavirus NL63 (HCoV-NL63) infection were previously described. The virus binds to target cells by heparan sulfate proteoglycans, and interacts with the ACE2 protein. Subsequent events, including virus internalization and trafficking, remain to be elucidated. In this study, we mapped the process of HCoV-NL63 entry into LLC-Mk2 cell line and ex vivo 3D tracheobronchial tissue.Using a variety of techniques we have shown that HCoV-NL63 virions require endocytosis for successful entry to the LLC-MK2 cells, and interaction between the virus and the ACE2 molecule triggers recruitment of clathrin...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29142021/inf2-mediated-actin-polymerization-at-the-er-stimulates-mitochondrial-calcium-uptake-inner-membrane-constriction-and-division
#7
Rajarshi Chakrabarti, Wei-Ke Ji, Radu V Stan, Jaime de Juan Sanz, Timothy A Ryan, Henry N Higgs
Mitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through ER-bound inverted formin 2 (INF2) stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter...
November 15, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29138354/efficient-er-fusion-requires-a-dimerization-and-c-terminal-tail-mediated-membrane-anchoring-of-rhd3
#8
Jiaqi Sun, Huanquan Zheng
The endoplasmic reticulum (ER) is a network of tubules and sheets stretching throughout the eukaryotic cells. The formation of the ER requires homotypic membrane fusion, which is mediated by a family of Dynamin-like GTPase proteins. The Arabidopsis member ROOT HAIR DEFECTIVE3 (RHD3) has been demonstrated to mediate ER membrane fusion, but how exactly RHD3 is involved in the process is still unknown. Here we conducted systemic structure-function analyses of roles of different RHD3 domains in mediating ER fusion...
November 14, 2017: Plant Physiology
https://www.readbyqxmd.com/read/29130937/amphiphysin-bin1-negatively-regulates-dynamin-2-for-normal-muscle-maturation
#9
Belinda S Cowling, Ivana Prokic, Hichem Tasfaout, Aymen Rabai, Frédéric Humbert, Bruno Rinaldi, Anne-Sophie Nicot, Christine Kretz, Sylvie Friant, Aurélien Roux, Jocelyn Laporte
Regulation of skeletal muscle development and organization is a complex process that is not fully understood. Here, we focused on amphiphysin 2 (BIN1, also known as bridging integrator-1) and dynamin 2 (DNM2), two ubiquitous proteins implicated in membrane remodeling and mutated in centronuclear myopathies (CNMs). We generated Bin1-/- Dnm2+/- mice to decipher the physiological interplay between BIN1 and DNM2. While Bin1-/- mice die perinatally from a skeletal muscle defect, Bin1-/- Dnm2+/- mice survived at least 18 months, and had normal muscle force and intracellular organization of muscle fibers, supporting BIN1 as a negative regulator of DNM2...
November 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29127384/targeting-c-kit-cd117-by-dasatinib-and-radotinib-promotes-acute-myeloid-leukemia-cell-death
#10
Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Yoo Kyung Jeong, Jae-Cheol Jo, Yunsuk Choi, SuJin Koh, Jin Ho Baek, Young Joo Min, Hawk Kim
Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90β (HSP90β) expression and release Apaf-1 in c-KIT-positive AML cells...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29110115/dnm1l-variant-alters-baseline-mitochondrial-function-and-response-to-stress-in-a-patient-with-severe-neurological-dysfunction
#11
Kaley A Hogarth, Sheila R Costford, Grace Yoon, Neal Sondheimer, Jason T Maynes
Mitochondria play vital roles in brain development and neuronal activity, and mitochondrial dynamics (fission and fusion) maintain organelle function through the removal of damaged components. Dynamin-like protein-1 (DRP-1), encoded by DNM1L, is an evolutionarily conserved GTPase that mediates mitochondrial fission by surrounding the scission site in concentric ring-like structures via self-oligomerization, followed by GTPase-dependant constriction. Here, we describe the clinical characteristics and cellular phenotype of a patient with severe neurological dysfunction, possessing a homozygous DNM1L variant c...
November 6, 2017: Biochemical Genetics
https://www.readbyqxmd.com/read/29105112/dynamin-2-associated-myopathy-with-electrical-but-not-clinical-myotonia
#12
Amro M Stino, Stanley J Iyadurai
No abstract text is available yet for this article.
November 3, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/29101235/mechanisms-and-modulation-of-microvesicle-uptake-in-a-model-of-alveolar-cell-communication
#13
Daniel J Schneider, Jennifer M Speth, Loka R Penke, Scott H Wettlaufer, Joel A Swanson, Marc Peters-Golden
Extracellular vesicles (EVs), including exosomes and shed microvesicles (MVs), can be internalized by recipient cells to modulate function. Although the mechanism by which EVs are internalized is incompletely characterized, it is generally regarded to involve endocytosis and an initial surface binding event. Furthermore, modulation of uptake by microenvironmental factors is largely unstudied. Here we used flow cytometry, confocal microscopy, and pharmacologic and molecular targeting to address these gaps in knowledge in a model of pulmonary alveolar cell-cell communication...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29093165/sequences-flanking-the-transmembrane-segments-facilitate-mitochondrial-localization-and-membrane-fusion-by-mitofusin
#14
Xiaofang Huang, Xin Zhou, Xiaoyu Hu, Amit S Joshi, Xiangyang Guo, Yushan Zhu, Quan Chen, William A Prinz, Junjie Hu
Mitochondria constantly divide and fuse. Homotypic fusion of the outer mitochondrial membranes requires the mitofusin (MFN) proteins, a family of dynamin-like GTPases. MFNs are anchored in the membrane by transmembrane (TM) segments, exposing both the N-terminal GTPase domain and the C-terminal tail (CT) to the cytosol. This arrangement is very similar to that of the atlastin (ATL) GTPases, which mediate fusion of endoplasmic reticulum (ER) membranes. We engineered various MFN-ATL chimeras to gain mechanistic insight into MFN-mediated fusion...
November 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29078380/large-g-protein-%C3%AE-subunit-xl%C3%AE-s-limits-clathrin-mediated-endocytosis-and-regulates-tissue-iron-levels-in-vivo
#15
Qing He, Richard Bouley, Zun Liu, Marc N Wein, Yan Zhu, Jordan M Spatz, Chia-Yu Wang, Paola Divieti Pajevic, Antonius Plagge, Jodie L Babitt, Murat Bastepe
Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by GNAS, XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29072687/guanylate-binding-protein-2-regulates-drp1-mediated-mitochondrial-fission-to-suppress-breast-cancer-cell-invasion
#16
Juan Zhang, Yu Zhang, Wenshuang Wu, Fang Wang, Xinyu Liu, Guanghou Shui, Chunlai Nie
Guanylate-binding protein 2 (GBP2) is a member of the large GTPase superfamily that is strongly induced by interferon-γ (IFN-γ). Although the biochemical characteristics of GBP2 have been reported in detail, its biological function has not been thoroughly elucidated to date. To the best of our knowledge, this study presents the first demonstration that GBP2 inhibits mitochondrial fission and cell metastasis in breast cancer cells both in vitro and in vivo. Our previous work demonstrated that dynamin-related protein 1 (Drp1)-dependent mitochondrial fission has a key role in breast cancer cell invasion...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29072685/sirt3-protects-hepatocytes-from-oxidative-injury-by-enhancing-ros-scavenging-and-mitochondrial-integrity
#17
Jingxin Liu, Dan Li, Tian Zhang, Qiang Tong, Richard Dequan Ye, Ligen Lin
Evidences of oxidative stress and mitochondrial dysfunction have been recognized in most of clinical and experimental liver diseases. SIRT3, a member of NAD(+)-dependent deacetylases, is mainly localized in mitochondria. So far, the role of SIRT3 in protecting hepatocytes against oxidative stress remains elusive. Herein, we found SIRT3 protein expression is decreased in tert-butyl hydroperoxide (t-BHP)-treated AML12 cells in vitro and primary hepatocytes from CCl4-injured mice in vivo. To further verify the role of SIRT3 in protecting hepatocytes from t-BHP-induced injury, SIRT3 overexpressed AML12 cell line and primary hepatocytes were generated...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29071728/impaired-excitation-contraction-coupling-in-muscle-fibres-from-the-dynamin2-r465w-mouse-model-of-centronuclear-myopathy
#18
Candice Kutchukian, Peter Szentesi, Bruno Allard, Delphine Trochet, Maud Beuvin, Christine Berthier, Yves Tourneur, Pascale Guicheney, Laszlo Csernoch, Marc Bitoun, Vincent Jacquemond
Mutations in the gene encoding dynamin 2 (DNM2) are responsible for autosomal dominant centronuclear myopathy (AD-CNM). We studied the functional properties of Ca(2+) signalling and excitation-contraction (EC) coupling in muscle fibres isolated from a knock-in (KI) mouse model of the disease, using confocal imaging and voltage-clamp. The transverse-tubule network organization looked unaltered in the diseased fibres but its density was reduced by ∼10% as compared to that in control fibres. The density of Ca(2+) current through CaV1...
October 26, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29068134/structure-function-and-regulation-of-mitofusin-2-in-health-and-disease
#19
Gursimran Chandhok, Michael Lazarou, Brent Neumann
Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis...
October 25, 2017: Biological Reviews of the Cambridge Philosophical Society
https://www.readbyqxmd.com/read/29052840/crowd-sourcing-of-membrane-fission-how-crowding-of-non-specialized-membrane-bound-proteins-contributes-to-cellular-membrane-fission
#20
REVIEW
Marco M Manni, Jure Derganc, Alenka Čopič
Fission of cellular membranes is ubiquitous and essential for life. Complex protein machineries, such as the dynamin and ESCRT spirals, have evolved to mediate membrane fission during diverse cellular processes, for example, vesicle budding. A new study suggests that non-specialized membrane-bound proteins can induce membrane fission through mass action due to protein crowding. Because up to 2/3 of the mass of cellular membranes is contributed by proteins, membrane protein crowding is an important physiological parameter...
October 20, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
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