Regulation of Antiviral Immunity by Mitochondrial Dynamics
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
During this process, two mitochondria fuse together to exchange membrane components and matrix proteins (Twig and Shirihai, 2011). Fusion often leads to balance the damage response in which a partially damaged mitochondrion fuses with a fully healthy mitochondrion and this fusion leads to dilute the damaged content accumulated in the impaired mitochondrion (Twig et al., 2008; Twig and Shirihai, 2011). In eukaryotic cells, a single mitochondrion can exist in pre-fusion and post-fusion phases. In pre-fusion stage, the mitochondria are solitary while post-fusion phase represent complex network of mitochondria (Twig et al., 2008). The first fusion regulatory protein, fuzzy onion (Fzo) was identified in Drosophila. Fzo deleted strain showed accumulation of fragmented mitochondria, which proved that Fzo can control mitochondrial fusion. In Fzo mutant flies, mitochondria aggregate and fail to fuse, which lead to the accumulation of fragmented mitochondria in spermatid (Hales and Fuller, 1997; Hermann et al., 1998). In mammals, the molecules that govern fusion machinery are Mitofusin 1/2 (Mfn1 and Mfn2) and Optic atrophy 1 protein (OPA1) (Khan et al., 2015). Elimination of any of these proteins leads to embryonic lethality and mitochondrial dysfunction (Chen et al., 2003). Mfn1 and Mfn2 are homologs of Fzo which have similar but distinct roles in mitochondrial morphology control (Chen et al., 2003). These are ubiquitously expressed and membrane anchored dynamin family proteins that are uniformly localized to the outer mitochondrial membrane (OMM).
Imaging of Intracellular Targets
George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos in Handbook of Small Animal Imaging, 2018
Large and hydrophilic molecules can enter the cell through different types of endocytosis, a process by which cells absorb molecules by invagination of the plasma membrane. Substances may be taken up by endocytosis after binding to a receptor, by interacting with other structures on the cell surface, or just by being engulfed together with fluid surrounding the cell when an endocytic vesicle is formed. There are multiple types of endocytic pathways of which the clathrin-mediated endocytosis pathway is best known and by far the best studied. Additionally, several clathrin-independent endocytosis mechanisms have been described (Sandvig et al. 2008; Howes et al. 2010; Kumari et al. 2010), including dynamin-dependent mechanisms and dynamin-independent mechanisms. It should be noted that receptor-mediated endocytosis can involve several of the aforementioned mechanisms, dependent on the type of receptor being used.
TRPML Subfamily of Endolysosomal Channels
Bruno Gasnier, Michael X. Zhu in Ion and Molecule Transport in Lysosomes, 2020
TRPMLs are endolysosomal membrane proteins. Fluorescently tagged TRPML1 is predominantly localized to late-endosomes and lysosomes as evidenced by colocalization with Rab7, lysosomal-associated membrane protein 1 (Lamp1), endolysosomal lipid LBPA, and LysoTracker (Manzoni et al., 2004; Thompson et al., 2007; Venkatachalam et al., 2006; Vergarajauregui and Puertollano, 2006). The TRPML1 ortholog in Drosophila also localizes to the membranes of late-endosomes and lysosomes (Venkatachalam et al., 2008; Wong et al., 2012). Human TRPML1 bears two di-leucine motifs that mediate the localization of the protein from the plasma membrane to endosomes (Venkatachalam et al., 2006; Vergarajauregui and Puertollano, 2006). Since expression of dominant-negative dynamin was sufficient to mislocalize TRPML1 to the cell surface, we envision that localization of TRPML1 to endolysosomal membrane requires internalization from the plasma membrane (Venkatachalam et al., 2006). However, TRPML1 can also be delivered to endocytic compartments directly from the trans-Golgi via a pathway mediated by adapter protein complex-1 (AP-1) (Vergarajauregui and Puertollano, 2006). The existence of multiple routes of endolysosomal delivery likely serves as a failsafe mechanism to ensure that TRPML1 reaches the endocytic compartment. Loss of MCOLN1 or its orthologs in different species results in accumulation of endolysosomes, which is a defining feature of lysosomal storage diseases such as MLIV (Figure 4.1).
Targeting Glioma Stem Cells by Functional Inhibition of Dynamin 2: A Novel Treatment Strategy for Glioblastoma
Published in Cancer Investigation, 2019
Rodney Luwor, Andrew P. Morokoff, Stephanie Amiridis, Giovanna D’Abaco, Lucia Paradiso, Stanley S. Stylli, Hong P. T. Nguyen, Mark Tarleton, Kelly A. Young, Terence J. O’Brien, Phillip J. Robinson, Megan Chircop, Adam McCluskey, Nigel C. Jones
Traditionally, dynamin 2 is well known for its role in endocytosis but it is also considered a major intracellular protein hub (18). This versatile protein directly interacts with PI3K, Src and FAK to facilitate complexes that aid motility, is involved in actin organisation, lamellipodia extension and is required for cell division and signalling, and secretion of matrix metalloproteinases – all of which have been implicated in tumorigenesis (19–24). Pharmacological inhibition of dynamin 2 by GTPase inhibitors has been shown to suppress specific cellular processes such as lamellipodia formation, migration and invasion of human osteocarcinoma cells and the growth of human prostate adenocarcinoma cells and human glioblastoma cells (20, 21, 25–27). Furthermore, overexpression of dynamin 2 is associated with poor prognosis in both pancreatic and prostate cancer and has already shown promise as a viable target in the treatment of pancreatic cancer, where dynamin 2 knockout mice displayed reduced tumorigenicity than wild-type mice (28, 29). Thus, this evidence raises the possibility that dynamin 2 may be a viable target in glioblastoma therapy.
Flavanol-rich lychee fruit extract substantially reduces progressive cognitive and molecular deficits in a triple-transgenic animal model of Alzheimer disease
Published in Nutritional Neuroscience, 2021
Xiao Chen, Benhong Xu, Luling Nie, Kaiwu He, Li Zhou, Xinfeng Huang, Peter Spencer, Xifei Yang, Jianjun Liu
Oligonol treatment also modulated the expression of synaptic proteins (DC1I1, dynamin-1, synapsin II and vimentin) in the hippocampi of 3×Tg-AD mice. DC1I1 transports cargos from axon terminals to neuron cell bodies [49]. Dynamin-1 releases intracellular substances from synaptic vesicles [50]. Synapsin II regulates the pool of synaptic vesicles [51]. Vimentin expression is related to synaptic damage [52]. In the present study, both dynamin-1 and synapsin II were reduced in 3×Tg-AD mice and increased by Oligonol treatment, whereas DC1I1 and vimentin were reduced. These findings together with evidence of observed alterations in Aβ and tau suggest synaptic damage, which could explain the associated memory dysfunction displayed by 3×Tg-AD mice [53,54]. In addition, dysfunction of the electron transport chain [55] and UPR [47] could exacerbate the synapse dysfunction. We observed a significant loss of synaptic proteins in 3×Tg-AD mice and the retention of some synaptic proteins with Oligonol treatment (Figure 3). The consistent findings from Western-blot analyses and the proteomics study suggest that Oligonol treatment maintained synaptic integrity and memory function.
Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs
Published in Expert Opinion on Drug Delivery, 2018
Renuka Suresh Managuli, Sushil Yadaorao Raut, Meka Sreenivasa Reddy, Srinivas Mutalik
Clathrin-mediated endocytosis involves the submerging of molecule into the cell plasma membrane which buds inward to form vesicles. Here, a GTPase called dynamin plays a major role in vesicle formation with involvement in the budding and scission process of nascent vesicles from parent membrane. The molecule filled budding vesicle is covered with 180 kDa proteins called clathrins which are triskelion, consisting of three heavy chains and three light chains. Many triskelion clathrins arrange into pentagon or hexagon structure surrounding the vesicle. Clathrin does not directly bind to the plasma membrane or to vesicle, instead adaptor proteins AP2, AP180, and epsin fuses clathrins to vesicles. The clathrin coating over vesicles is then detached thereby releasing the vesicles into endosomes. Synaptic vesicle uptake in neurons is an example of clathrin-mediated endocytosis [47,48]. Caveolae are cholesterol and sphingolipid rich plasma membrane’s inward growth vesicles coated with caveolin-1 protein [49]. Clathrin and caveolae independent endocytosis do not involve the clathrin or caveolae coating over pits. Chlorpromazine and nystatin are clathrin and caveolae-mediated endocytosis inhibitors, respectively, which are used in depicting the absorption mechanism of nanoparticles [50–52]. The Soluplus®/TPGS binary mixed micelle system prepared by Hu et al. [53], showed lymphatic transport in cycloheximide rat model and suggested lipid raft/caveolae and macropinocytosis-mediated the cell uptake through P-glycoprotein (P-gp)-independent pathway.
Related Knowledge Centers
- Caveolae
- Golgi Apparatus
- Gtpase
- Vesicle
- Cytokinesis
- Organelle
- Pathogen
- Endocytosis
- Dynamin Superfamily
- Guanylate-Binding Protein