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Pasquale Picone, Silvia Vilasi, Fabio Librizzi, Marco Contardi, Domenico Nuzzo, Luca Caruana, Sara Baldassano, Antonella Amato, Flavia Mulè, Pier Luigi San Biagio, Daniela Giacomazza, Marta Di Carlo
The onset of Alzheimer disease (AD) is influenced by several risk factors comprising diabetes. Within this context, antidiabetic drugs, including metformin, are investigated for their effect on AD. We report that in the C57B6/J mice, metformin is delivered to the brain where activates AMP-activated kinase (AMPK), its molecular target. This drug affects the levels of β-secretase (BACE1) and β-amyloid precursor protein (APP), promoting processing and aggregation of β-amyloid (Aβ), mainly in the cortex region...
August 2016: Aging
John O Ogunbileje, Craig Porter, David N Herndon, Tony Chao, Doaa R Abdelrahman, Anastasia Papadimitriou, Maria Chondronikola, Teresa A Zimmers, Paul T Reidy, Blake B Rasmussen, Labros S Sidossis
Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria...
August 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
Andrea Magrì, Maria Carmela Di Rosa, Marianna Flora Tomasello, Francesca Guarino, Simona Reina, Angela Messina, Vito De Pinto
Cu/Zn Superoxide Dismutase (SOD1), the most important antioxidant defense against ROS in eukaryotic cells, localizes in cytosol and intermembrane space of mitochondria (IMS). Several evidences show a SOD1 intersection with both fermentative and respiratory metabolism. The Voltage Dependent Anion Channel (VDAC) is the main pore-forming protein in the mitochondrial outer membrane (MOM), and is considered the gatekeeper of mitochondrial metabolism. Saccharomyces cerevisiae lacking VDAC1 (Δpor1) is a very convenient model system, since it shows an impaired growth rate on non-fermentable carbon source...
June 2016: Biochimica et Biophysica Acta
Morgane Michaud, Valérie Gros, Marianne Tardif, Sabine Brugière, Myriam Ferro, William A Prinz, Alexandre Toulmay, Jaideep Mathur, Michael Wozny, Denis Falconet, Eric Maréchal, Maryse A Block, Juliette Jouhet
The mitochondrion is an organelle originating from an endosymbiotic event and playing a role in several fundamental processes such as energy production, metabolite syntheses, and programmed cell death. This organelle is delineated by two membranes whose synthesis requires an extensive exchange of phospholipids with other cellular organelles such as endoplasmic reticulum (ER) and vacuolar membranes in yeast. These transfers of phospholipids are thought to occur by a non-vesicular pathway at contact sites between two closely apposed membranes...
March 7, 2016: Current Biology: CB
Jan Mani, Chris Meisinger, André Schneider
Mitochondria are essential for eukaryotic life and more than 95% of their proteins are imported as precursors from the cytosol. The targeting signals for this posttranslational import are conserved in all eukaryotes. However, this conservation does not hold true for the protein translocase of the mitochondrial outer membrane that serves as entry gate for essentially all precursor proteins. Only two of its subunits, Tom40 and Tom22, are conserved and thus likely were present in the last eukaryotic common ancestor...
February 2016: Molecular Biology and Evolution
Sriram Garg, Jan Stölting, Verena Zimorski, Petr Rada, Jan Tachezy, William F Martin, Sven B Gould
The origin of protein import was a key step in the endosymbiotic acquisition of mitochondria. Though the main translocon of the mitochondrial outer membrane, TOM40, is ubiquitous among organelles of mitochondrial ancestry, the transit peptides, or N-terminal targeting sequences (NTSs), recognised by the TOM complex, are not. To better understand the nature of evolutionary conservation in mitochondrial protein import, we investigated the targeting behavior of Trichomonas vaginalis hydrogenosomal proteins in Saccharomyces cerevisiae and vice versa...
September 2015: Genome Biology and Evolution
Adam J Kuszak, Daniel Jacobs, Philip A Gurnev, Takuya Shiota, John M Louis, Trevor Lithgow, Sergey M Bezrukov, Tatiana K Rostovtseva, Susan K Buchanan
Nearly all mitochondrial proteins are coded by the nuclear genome and must be transported into mitochondria by the translocase of the outer membrane complex. Tom40 is the central subunit of the translocase complex and forms a pore in the mitochondrial outer membrane. To date, the mechanism it utilizes for protein transport remains unclear. Tom40 is predicted to comprise a membrane-spanning β-barrel domain with conserved α-helical domains at both the N and C termini. To investigate Tom40 function, including the role of the N- and C-terminal domains, recombinant forms of the Tom40 protein from the yeast Candida glabrata, and truncated constructs lacking the N- and/or C-terminal domains, were functionally characterized in planar lipid membranes...
October 23, 2015: Journal of Biological Chemistry
Małgorzata Wojtkowska, Dorota Buczek, Olgierd Stobienia, Andonis Karachitos, Monika Antoniewicz, Małgorzata Slocinska, Wojciech Makałowski, Hanna Kmita
Protein import into mitochondria requires a wide variety of proteins, forming complexes in both mitochondrial membranes. The TOM complex (translocase of the outer membrane) is responsible for decoding of targeting signals, translocation of imported proteins across or into the outer membrane, and their subsequent sorting. Thus the TOM complex is regarded as the main gate into mitochondria for imported proteins. Available data indicate that mitochondria of representative organisms from across the major phylogenetic lineages of eukaryotes differ in subunit organization of the TOM complex...
July 2015: Protist
Piotr Bragoszewski, Michal Wasilewski, Paulina Sakowska, Agnieszka Gornicka, Lena Böttinger, Jian Qiu, Nils Wiedemann, Agnieszka Chacinska
The content of mitochondrial proteome is maintained through two highly dynamic processes, the influx of newly synthesized proteins from the cytosol and the protein degradation. Mitochondrial proteins are targeted to the intermembrane space by the mitochondrial intermembrane space assembly pathway that couples their import and oxidative folding. The folding trap was proposed to be a driving mechanism for the mitochondrial accumulation of these proteins. Whether the reverse movement of unfolded proteins to the cytosol occurs across the intact outer membrane is unknown...
June 23, 2015: Proceedings of the National Academy of Sciences of the United States of America
Daniel O Frank, Jörn Dengjel, Florian Wilfling, Vera Kozjak-Pavlovic, Georg Häcker, Arnim Weber
The pro-apoptotic Bcl-2-family protein Bim belongs to the BH3-only proteins known as initiators of apoptosis. Recent data show that Bim is constitutively inserted in the outer mitochondrial membrane via a C-terminal transmembrane anchor from where it can activate the effector of cytochrome c-release, Bax. To identify regulators of Bim-activity, we conducted a search for proteins interacting with Bim at mitochondria. We found an interaction of Bim with Tom70, Tom20 and more weakly with Tom40, all components of the Translocase of the Outer Membrane (TOM)...
2015: PloS One
William K Gottschalk, Michael W Lutz, Yu Ting He, Ann M Saunders, Daniel K Burns, Allen D Roses, Ornit Chiba-Falek
Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD (TOMM40) is associated with risk and age-of onset of late-onset AD, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction. In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases...
November 2014: Journal of Parkinson's Disease and Alzheimer's Disease
Kei Okatsu, Mayumi Kimura, Toshihiko Oka, Keiji Tanaka, Noriyuki Matsuda
Dysfunction of PTEN-induced putative kinase 1 (PINK1), a Ser/Thr kinase with an N-terminal mitochondrial-targeting sequence (MTS), causes familial recessive parkinsonism. Reduction of the mitochondrial membrane potential limits MTS-mediated matrix import and promotes PINK1 accumulation on the outer mitochondrial membrane (OMM) of depolarized mitochondria. PINK1 then undergoes autophosphorylation and phosphorylates ubiquitin and Parkin, a cytosolic ubiquitin ligase, for clearance of damaged mitochondria. The molecular basis for PINK1 localization on the OMM of depolarized mitochondria rather than release to the cytosol is poorly understood...
March 1, 2015: Journal of Cell Science
Angelika B Harbauer, Magdalena Opalińska, Carolin Gerbeth, Josip S Herman, Sanjana Rao, Birgit Schönfisch, Bernard Guiard, Oliver Schmidt, Nikolaus Pfanner, Chris Meisinger
Mitochondria play central roles in cellular energy conversion, metabolism, and apoptosis. Mitochondria import more than 1000 different proteins from the cytosol. It is unknown if the mitochondrial protein import machinery is connected to the cell division cycle. We found that the cyclin-dependent kinase Cdk1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. The molecular mechanism involved phosphorylation of the cytosolic precursor of Tom6 by cyclin Clb3-activated Cdk1, leading to enhanced import of Tom6 into mitochondria...
November 28, 2014: Science
Xuejun Yao, Ulrich H N Dürr, Zrinka Gattin, Yvonne Laukat, Rhagavendran L Narayanan, Ann-Kathrin Brückner, Chris Meisinger, Adam Lange, Stefan Becker, Markus Zweckstetter
Membrane proteins play key roles in biology. Determination of their structure in a membrane environment, however, is highly challenging. To address this challenge, we developed an approach that couples hydrogen/deuterium exchange of membrane proteins to rapid unfolding and detection by solution-state NMR spectroscopy. We show that the method allows analysis of the solvent protection of single residues in liposome-embedded proteins such as the 349-residue Tom40, the major protein translocation pore in the outer mitochondrial membrane, which has resisted structural analysis for many years...
2014: PloS One
Agnieszka Gornicka, Piotr Bragoszewski, Piotr Chroscicki, Lena-Sophie Wenz, Christian Schulz, Peter Rehling, Agnieszka Chacinska
Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway...
December 15, 2014: Molecular Biology of the Cell
Takuma Yoshizumi, Takeshi Ichinohe, Osamu Sasaki, Hidenori Otera, Shun-ichiro Kawabata, Katsuyoshi Mihara, Takumi Koshiba
Mitochondria contribute to cellular innate immunity against RNA viruses. Mitochondrial-mediated innate immunity is regulated by signalling molecules that are recruited to the mitochondrial membrane, and depends on the mitochondrial inner membrane potential (Δψm). Here we examine the physiological relevance of Δψm and the mitochondrial-associating influenza A viral protein PB1-F2 in innate immunity. When expressed in host cells, PB1-F2 completely translocates into the mitochondrial inner membrane space via Tom40 channels, and its accumulation accelerates mitochondrial fragmentation due to reduced Δψm...
2014: Nature Communications
Jonathan Melin, Christian Schulz, Lidia Wrobel, Olaf Bernhard, Agnieszka Chacinska, Olaf Jahn, Bernhard Schmidt, Peter Rehling
More than 70% of mitochondrial proteins utilize N-terminal presequences as targeting signals. Presequence interactions with redundant cytosolic receptor domains of the translocase of the outer mitochondrial membrane (TOM) are well established. However, after the presequence enters the protein-conducting Tom40 channel, the recognition events that occur at the trans side leading up to the engagement of the presequence with inner membrane-bound receptors are less well defined. Using a photoaffinity-labeling approach with modified presequence peptides, we identified Tom40 as a presequence interactor of the TOM complex...
September 15, 2014: Molecular and Cellular Biology
Márcio Ribeiro, Tatiana R Rosenstock, Ana M Oliveira, Catarina R Oliveira, A Cristina Rego
Oxidative stress and mitochondrial dysfunction have been described in Huntington's disease, a disorder caused by expression of mutant huntingtin (mHtt). IGF-1 was previously shown to protect HD cells, whereas insulin prevented neuronal oxidative stress. In this work we analyzed the role of insulin and IGF-1 in striatal cells derived from HD knock-in mice on mitochondrial production of reactive oxygen species (ROS) and related antioxidant and signaling pathways influencing mitochondrial function. Insulin and IGF-1 decreased mitochondrial ROS induced by mHtt and normalized mitochondrial SOD activity, without affecting intracellular glutathione levels...
September 2014: Free Radical Biology & Medicine
Sebastian W K Lackey, Rebecca D Taylor, Nancy E Go, Annie Wong, E Laura Sherman, Frank E Nargang
Most proteins found in mitochondria are translated in the cytosol and enter the organelle via the TOM complex (translocase of the outer mitochondrial membrane). Tom40 is the pore forming component of the complex. Although the three-dimensional structure of Tom40 has not been determined, the structure of porin, a related protein, has been shown to be a β-barrel containing 19 membrane spanning β-strands and an N-terminal α-helical region. The evolutionary relationship between the two proteins has allowed modeling of Tom40 into a similar structure by several laboratories...
August 1, 2014: Journal of Biological Chemistry
Felix Schnarwiler, Moritz Niemann, Nicholas Doiron, Anke Harsman, Sandro Käser, Jan Mani, Astrid Chanfon, Caroline E Dewar, Silke Oeljeklaus, Christopher B Jackson, Mascha Pusnik, Oliver Schmidt, Chris Meisinger, Sebastian Hiller, Bettina Warscheid, Achim C Schnaufer, Torsten Ochsenreiter, André Schneider
Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a β-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum-mitochondria encounter structure (ERMES)...
May 27, 2014: Proceedings of the National Academy of Sciences of the United States of America
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