Regulation of Antiviral Immunity by Mitochondrial Dynamics
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Mitochondrial fusion occurs via fusion of the outer and inner mitochondrial membrane (IMM) which results in the union of two separate mitochondrion and simultaneous mixing of their inner contents (Santel and Fuller, 2001). Mfn1 and Mfn2 coordinate OMM fusion while the IMM fusion is mediated by Opa1. Mutation in any of these proteins can cause abnormal mitochondrial morphology and remarkable reduction in mitochondrial fusion (Chen and Chan, 2009; Chen et al., 2005). Mfn1 and Mfn2 depleted cells showed poor cell growth, decreased cellular respiration associated with the heterogeneity of mitochondrial membrane potential (Chan, 2012). OPA1; a dynamin-related GTPase is localized in the inner mitochondrial membrane (IMM) of many mammalian cells and orchestrate IMM fusion (Frezza et al., 2006). OPA1 protein plays multiple important roles in mitochondrial cristae architecture, bioenergetics and apoptosis (Frezza et al., 2006; Head et al., 2009). The presence of Mfns on both the fusing mitochondria is the prerequisite for outer membrane fusion. Oligomerization of the Mfn1/2 on adjacent mitochondria brings the opposing membranes within close proximity and by membrane fusion, it eventually promotes fusion. Homotypic and heterotypic physical interaction between Mfn1/2 result in Mfn1 homotypic oligomers, Mfn2 homotypic oligomers and Mfn1–Mfn2 heterotypic oligomers (Chen et al., 2003).
The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle
Chad Cox in Clinical Nutrition and Aging, 2017
Mitochondrial fusion and fission contribute to mitochondrial function by exchanging components such as membrane, proteins, and DNA. Mitochondrial fission and fusion are regulated by GTPases of the Dynamin family, with opposite functions. Fission is mediated by dynamin related protein 1 (Drp1) and plays a key role in maintaining mitochondrial quality and mtDNA integrity, as it allows dysfunctional mitochondria to be severed from the network and to be removed by autophagy. Fusion is controlled by optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2 [101, 102]). Opa1 is also involved in degradative processes; indeed it regulates apoptosis by keeping the inner mitochondrial cristae junctions tight to prevent cytochrome c release, which characterizes apoptosis [103]. Few recent studies have reported that Mfn2 gene expression is lower in the skeletal muscle of older humans [63].
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.
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.
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.
Delivery of pDNA to lung epithelial cells using PLGA nanoparticles formulated with a cell-penetrating peptide: understanding the intracellular fate
Published in Drug Development and Industrial Pharmacy, 2020
Larissa Gomes dos Reis, Wing-Hin Lee, Maree Svolos, Lyn M. Moir, Rima Jaber, Andrea Engel, Norbert Windhab, Paul M. Young, Daniela Traini
Chlorpromazine, an inhibitor that disrupts the formation of clathrin-coated pits, hence inhibiting clathrin-mediated endocytosis, led to the most significant decrease in NP–DNA–CPP uptake in both cell lines, with only 22% of positive cells in A549 and 67% in Beas-2B, respectively. To a lesser extent, the disruption of microtubules formation via the microtubule depolymerizing agent nocodazole also significantly decreases internalization to ∼63% in both cell lines. The inhibition of GTPase activity dynamin was also able to significantly decrease NP–DNA–CPP uptake in both cell lines. Dynamin is essential for membrane fission of clathrin-coated vesicles [18] and also plays a role on caveola-mediated and lipid-raft endocytosis [16]. Wortmannin, a pharmacological inhibitor that affects the formation of the double-shell of the endosomes, hence inhibiting clathrin-mediated endocytosis, led to a significant decrease by 20 and 25% of NP–DNA–CPP uptake in A549 and Beas-2B respectively. When colchicine was used to bind tubulin, thereby inhibiting cytoskeleton function, a significant decrease in A549 internalization was observed. Similarly, incubation with cytochalasin D decreased internalization to 61% of NP–DNA–CPP in A549. While the depletion of cholesterol in the cellular membrane caused by MβCD and the inhibition of scavenger receptors by Polyisinosinic acid did not affect internalization in A549, a decrease by 16 and 14%, respectively, was observed in Beas-2B.
Related Knowledge Centers
- Caveolae
- Golgi Apparatus
- Gtpase
- Vesicle
- Cytokinesis
- Organelle
- Pathogen
- Endocytosis
- Dynamin Superfamily
- Guanylate-Binding Protein