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Mitochondrial supercomplexes

Sergio Guerrero-Castillo, Fabian Baertling, Daniel Kownatzki, Hans J Wessels, Susanne Arnold, Ulrich Brandt, Leo Nijtmans
Mitochondrial complex I is the largest integral membrane enzyme of the respiratory chain and consists of 44 different subunits encoded in the mitochondrial and nuclear genome. Its biosynthesis is a highly complicated and multifaceted process involving at least 14 additional assembly factors. How these subunits assemble into a functional complex I and where the assembly factors come into play is largely unknown. Here, we applied a dynamic complexome profiling approach to elucidate the assembly of human mitochondrial complex I and its further incorporation into respiratory chain supercomplexes...
September 30, 2016: Cell Metabolism
Yasuhiro Horibata, Hiromi Ando, Peixiang Zhang, Laurent Vergnes, Chieko Aoyama, Masahiko Itoh, Karen Reue, Hiroyuki Sugimoto
Phosphatidylcholine (PC) is a major phospholipid of mitochondria, composing 40-50% of both the outer and the inner membranes. However, PC must be imported from its production organelles because mitochondria lack the enzymes essential for PC biosynthesis. In a previous study, we found that StarD7 mediates the intracellular transfer of PC to mitochondria. Therefore, in this study, we analyzed the contribution of StarD7 to the maintenance of mitochondrial phospholipid content and function using siRNA-mediated knockdown (KD) and knockout (KO) of the StarD7 gene in HEPA-1 cells...
September 30, 2016: Journal of Biological Chemistry
Katharina Roempler, Tobias Mueller, Lisa Juris, Mirjam Wissel, Milena Vukotic, Kay Hofmann, Markus Deckers
The mitochondrial electron transport chain (ETC) consists of individual protein complexes arranged into large macromolecular structures, termed respiratory chain supercomplexes or respirasomes. In the yeast Saccharomyces cerevisiae respiratory chain supercomplexes form by association of the bc1-complex with the cytochrome c oxidase. Formation and maintenance of these assemblies are promoted by specific respiratory supercomplex factors, the Rcf proteins. For these proteins a regulatory function in bridging the electron transfer within supercomplexes has been proposed...
September 23, 2016: Journal of Biological Chemistry
David A Stroud, Elliot E Surgenor, Luke E Formosa, Boris Reljic, Ann E Frazier, Marris G Dibley, Laura D Osellame, Tegan Stait, Traude H Beilharz, David R Thorburn, Agus Salim, Michael T Ryan
Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the mitochondrial respiratory chain and is composed of 45 subunits in humans, making it one of the largest known multi-subunit membrane protein complexes. Complex I exists in supercomplex forms with respiratory chain complexes III and IV, which are together required for the generation of a transmembrane proton gradient used for the synthesis of ATP. Complex I is also a major source of damaging reactive oxygen species and its dysfunction is associated with mitochondrial disease, Parkinson's disease and ageing...
September 14, 2016: Nature
Irina A Smirnova, Dan Sjöstrand, Fei Li, Markus Björck, Jacob Schäfer, Henrik Östbye, Martin Högbom, Christoph von Ballmoos, Gabriel C Lander, Pia Ädelroth, Peter Brzezinski
We used the amphipathic styrene maleic acid (SMA) co-polymer to extract cytochrome c oxidase (CytcO) in its native lipid environment from S. cerevisiae mitochondria. Native nanodiscs containing one CytcO per disc were purified using affinity chromatography. The longest cross-sections of the native nanodiscs were 11nm×14nm. Based on this size we estimated that each CytcO was surrounded by ~100 phospholipids. The native nanodiscs contained the same major phospholipids as those found in the mitochondrial inner membrane...
September 13, 2016: Biochimica et Biophysica Acta
Sehwan Jang, Taber S Lewis, Corey Powers, Zaza Khuchua, Christopher P Baines, Peter Wipf, Sabzali Javadov
<b>Aims:</b> Mitochondrial supercomplexes (SCs) are the large supramolecular assembly of individual electron transport chain (ETC) complexes that apparently provide highly efficient ATP synthesis and reduce electron leakage and ROS production. Oxidative stress during cardiac ischemia-reperfusion (IR) can result in degradation of SCs through oxidation of cardiolipin. Also, IR induces calcium overload, and enhances reactive oxygen species (mitROS) in mitochondria that result in the opening of the non-selective permeability transition pores (PTP)...
September 7, 2016: Antioxidants & Redox Signaling
Kezhong Zhang, Guohui Wang, Xuebao Zhang, Philipp P Hüttemann, Yining Qiu, Jenney Liu, Allison Mitchell, Icksoo Lee, Chao Zhang, Jin-Sook Lee, Petr Pecina, Guojun Wu, Zeng-Quan Yang, Maik Hüttemann, Lawrence I Grossman
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, plays a key role in regulating mitochondrial energy production and cell survival. COX subunit VIIa polypeptide 2-like protein (COX7AR) is a novel COX subunit that was recently found to be involved in mitochondrial supercomplex assembly and mitochondrial respiration activity. Here, we report that COX7AR is expressed in high energy-demanding tissues, such as brain, heart, liver, and aggressive forms of human breast cancer cells...
2016: Scientific Reports
Rafael Pérez-Pérez, Teresa Lobo-Jarne, Dusanka Milenkovic, Arnaud Mourier, Ana Bratic, Alberto García-Bartolomé, Erika Fernández-Vizarra, Susana Cadenas, Aitor Delmiro, Inés García-Consuegra, Joaquín Arenas, Miguel A Martín, Nils-Göran Larsson, Cristina Ugalde
Mitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain...
August 30, 2016: Cell Reports
Elina Welchen, Jessica Schmitz, Philippe Fuchs, Lucila García, Stephan Wagner, Judith Wienstroer, Peter Schertl, Hans-Peter Braun, Markus Schwarzländer, Daniel H Gonzalez, Veronica G Maurino
Glycolysis generates methylglyoxal (MGO) as an unavoidable, cytotoxic by-product in plant cells. MGO scavenging is performed by the glyoxalase system, which produces d-lactate as an end product. d-Lactate dehydrogenase (d-LDH) is encoded by a single gene in Arabidopsis (Arabidopsis thaliana; At5g06580). It catalyzes in vitro the oxidation of d-lactate to pyruvate using flavin adenine dinucleotide as a cofactor; knowledge of its function in the context of the plant cell remains sketchy. Blue native-polyacrylamide gel electrophoresis of mitochondrial extracts combined with in gel activity assays using different substrates and tandem mass spectrometry allowed us to definitely show that d-LDH acts specifically on d-lactate, is active as a dimer, and does not associate with respiratory supercomplexes of the inner mitochondrial membrane...
October 2016: Plant Physiology
Led Yered Jafet García Montes de Oca, Tecilli Cabellos Avelar, Gerardo Ignacio Picón Garrido, Alicia Chagoya-López, Luis González de la Vara, Norma Laura Delgado Buenrostro, Yolanda Irasema Chirino-López, Carlos Gómez-Lojero, Emma Berta Gutiérrez-Cirlos
The associations among respiratory complexes in energy-transducing membranes have been established. In fact, it is known that the Gram-negative bacteria Paracoccus denitrificans and Escherichia coli have respiratory supercomplexes in their membranes. These supercomplexes are important for channeling substrates between enzymes in a metabolic pathway, and the assembly of these supercomplexes depends on the protein subunits and membrane lipids, mainly cardiolipin, which is present in both the mitochondrial inner membrane and bacterial membranes...
August 2016: Journal of Bioenergetics and Biomembranes
Laura K Cole, Edgar M Meija, Marilyne Vandel, Genevieve C Sparagna, Steven M Claypool, Laura Dyck-Chan, Julianne Klein, Grant M Hatch
Mitochondria are the nexus of energy metabolism and consequently their dysfunction has been implicated in the development of metabolic complications and the progression to insulin resistance and type II diabetes. The unique tetra-acyl phospholipid cardiolipin (CL) is located in the inner mitochondrial membrane where it maintains mitochondrial integrity. Here we show that knock-down of Tafazzin (TAZ kd), a CL transacylase, in mice results in protection against the development of obesity, insulin resistance and hepatic steatosis...
August 5, 2016: Diabetes
Ruchika Anand, Valentina Strecker, Jennifer Urbach, Ilka Wittig, Andreas S Reichert
Mitochondrial cristae are connected to the inner boundary membrane via crista junctions which are implicated in the regulation of oxidative phosphorylation, apoptosis, and import of lipids and proteins. The MICOS complex determines formation of crista junctions. We performed complexome profiling and identified Mic13, also termed Qil1, as a subunit of the MICOS complex. We show that MIC13 is an inner membrane protein physically interacting with MIC60, a central subunit of the MICOS complex. Using the CRISPR/Cas method we generated the first cell line deleted for MIC13...
2016: PloS One
Katarzyna Kuter, Manuela Kratochwil, Sven-Hendric Marx, Sonja Hartwig, Stephan Lehr, Michiru D Sugawa, Norbert A Dencher
Cause of Parkinson's disease (PD) is still not understood. Motor symptoms are not observed at early stages of disease due to compensatory processes. Dysfunction of mitochondria was indicated already at preclinical PD. Selective toxin 6-OHDA was applied to kill dopaminergic neurons in substantia nigra and disturb neuronal transmission in striatum. Early phase of active degeneration and later stage, when surviving cells adapted to function normally, were analysed. 2D BN/SDS difference gel electrophoresis (DIGE) of mitochondrial proteome enabled to point out crucial processes involved at both time-points in dopaminergic structures...
July 28, 2016: Archives of Physiology and Biochemistry
Estefanía Piñero-Martos, Bernardo Ortega-Vila, Josep Pol-Fuster, Eugenia Cisneros-Barroso, Laura Ruiz-Guerra, Aina Medina-Dols, Damián Heine-Suñer, Jerònia Lladó, Gabriel Olmos, Cristofol Vives-Bauzà
Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the "Mitochondrial contact site and Cristae Organizing system" (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network...
July 27, 2016: Human Molecular Genetics
Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui
AIMS: Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI)...
September 2016: Cardiovascular Research
Camilla Rydström Lundin, Christoph von Ballmoos, Martin Ott, Pia Ädelroth, Peter Brzezinski
The respiratory supercomplex factors (Rcf) 1 and 2 mediate supramolecular interactions between mitochondrial complexes III (ubiquinol-cytochrome c reductase; cyt. bc1) and IV (cytochrome c oxidase; CytcO). In addition, removal of these polypeptides results in decreased activity of CytcO, but not of cyt. bc1 In the present study, we have investigated the kinetics of ligand binding, the single-turnover reaction of CytcO with O2, and the linked cyt. bc1-CytcO quinol oxidation-oxygen-reduction activities in mitochondria in which Rcf1 or Rcf2 were removed genetically (strains rcf1Δ and rcf2Δ, respectively)...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
David J Pagliarini
New "omics" tools are accelerating our ability to connect genomic variation to complex traits. Williams et al. (2016) reveal the power of layering quantitative proteomics and metabolomics measurements into a "systems genetics" analysis of recombinant inbred mouse strains to unravel new aspects of mitochondrial metabolism.
July 12, 2016: Cell Metabolism
Max-Hinderk Schuler, Francesca Di Bartolomeo, Christoph U Mårtensson, Günther Daum, Thomas Becker
Two protein translocases transport precursor proteins into or across the inner mitochondrial membrane. The presequence translocase (TIM23 complex) sorts precursor proteins with a cleavable presequence either into the matrix or into the inner membrane. The carrier translocase (TIM22 complex) inserts multispanning proteins into the inner membrane. Both protein import pathways depend on the presence of a membrane potential, which is generated by the activity of the respiratory chain. The non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine are required for the activity of the respiratory chain and therefore to maintain the membrane potential for protein import...
September 2, 2016: Journal of Biological Chemistry
Rob C I Wüst, Heder J de Vries, Liesbeth T Wintjes, Richard J Rodenburg, Hans W M Niessen, Ger J M Stienen
AIMS: In cardiac hypertrophy (CH) and heart failure (HF), alterations occur in mitochondrial enzyme content and activities but the origin and implications of these changes for mitochondrial function need to be resolved. METHODS AND RESULTS: Right ventricular CH or HF was induced by monocrotaline injection, which causes pulmonary artery hypertension, in rats. Results were compared with saline injection (CON). NAD(P)H and FAD autofluorescence were recorded in thin intact cardiac trabeculae during transitions in stimulation frequency, to assess mitochondrial complex I and complex II function, respectively...
September 2016: Cardiovascular Research
Lilli Winter, Ilka Wittig, Viktoriya Peeva, Britta Eggers, Juliana Heidler, Frederic Chevessier, Rudolf A Kley, Katalin Barkovits, Valentina Strecker, Carolin Berwanger, Harald Herrmann, Katrin Marcus, Cornelia Kornblum, Wolfram S Kunz, Rolf Schröder, Christoph S Clemen
Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive. To address this issue for protein aggregate myopathies, we performed a comprehensive, multi-level analysis of mitochondrial pathology in skeletal muscles of human patients with mutations in the intermediate filament protein desmin and in muscles of hetero- and homozygous knock-in mice carrying the R349P desmin mutation...
September 2016: Acta Neuropathologica
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