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Julia Bruggisser, Sandro Käser, Jan Mani, André Schneider
The mitochondrial outer membrane (OM) contains single and multiple membrane-spanning proteins that need to contain signals that ensure correct targeting and insertion into the OM. The biogenesis of such proteins has so far essentially only been studied in yeast and related organisms. Here we show that POMP10, an OM protein of the early diverging protozoan Trypanosoma brucei, is signal-anchored. Transgenic cells expressing variants of POMP10 fused to GFP demonstrate that the N-terminal membrane-spanning domain flanked by a few positively charged or neutral residues is both necessary and sufficient for mitochondrial targeting...
February 24, 2017: Journal of Biological Chemistry
Jan Mani, Samuel Rout, Silvia Desy, André Schneider
The β-barrel protein Tom40 and the α-helically anchored membrane protein Tom22 are the only universally conserved subunits of the protein translocase of the mitochondrial outer membrane (TOM). Tom22 has an N-terminal cytosolic and a C-terminal intermembrane space domain. It occurs in two variants: one typified by the yeast protein which has a cytosolic domain containing a cluster of acidic residues, and a shorter variant typified by the plant protein that lacks this domain. Yeast-type Tom22 functions as a secondary protein import receptor and is also required for the stability of the TOM complex...
January 17, 2017: Scientific Reports
Nargis Parvin, Chris Carrie, Isabelle Pabst, Antonia Läßer, Debabrata Laha, Melanie V Paul, Peter Geigenberger, Ralf Heermann, Kirsten Jung, Ute C Vothknecht, Fatima Chigri
The translocon on the outer membrane of mitochondria (TOM) facilitates the import of nuclear-encoded proteins. The principal machinery of mitochondrial protein transport seems conserved in eukaryotes; however, divergence in the composition and structure of TOM components has been observed between mammals, yeast, and plants. TOM9, the plant homolog of yeast Tom22, is significantly smaller due to a truncation in the cytosolic receptor domain, and its precise function is not understood. Here we provide evidence showing that TOM9...
April 3, 2017: Molecular Plant
Samuel Rout, Jon Paulin Zumthor, Elisabeth M Schraner, Carmen Faso, Adrian B Hehl
Protozoan parasites of the genus Giardia are highly prevalent globally, and infect a wide range of vertebrate hosts including humans, with proliferation and pathology restricted to the small intestine. This narrow ecological specialization entailed extensive structural and functional adaptations during host-parasite co-evolution. An example is the streamlined mitosomal proteome with iron-sulphur protein maturation as the only biochemical pathway clearly associated with this organelle. Here, we applied techniques in microscopy and protein biochemistry to investigate the mitosomal membrane proteome in association to mitosome homeostasis...
December 2016: PLoS Pathogens
Lu Li, Szymon Kubiszewski-Jakubiak, Jordan Radomiljac, Yan Wang, Simon R Law, Olivier Keech, Reena Narsai, Oliver Berkowitz, Owen Duncan, Monika W Murcha, James Whelan
In plant cells, mitochondria are major providers of energy and building blocks for growth and development as well as abiotic and biotic stress responses. They are encircled by two lipid membranes containing proteins that control mitochondrial function through the import of macromolecules and metabolites. Characterization of a novel β-barrel protein, OUTER MEMBRANE PROTEIN 47 (OM47), unique to the green lineage and related to the voltage-dependent anion channel (VDAC) protein family, showed that OM47 can complement a VDAC mutant in yeast...
November 2016: Journal of Experimental Botany
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
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