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Mitochondrial supercomplexes

Karen M Davies, Thorsten B Blum, Werner Kühlbrandt
We used electron cryo-tomography and subtomogram averaging to investigate the structure of complex I and its supramolecular assemblies in the inner mitochondrial membrane of mammals, fungi, and plants. Tomographic volumes containing complex I were averaged at ∼4 nm resolution. Principal component analysis indicated that ∼60% of complex I formed a supercomplex with dimeric complex III, while ∼40% were not associated with other respiratory chain complexes. The mutual arrangement of complex I and III2 was essentially conserved in all supercomplexes investigated...
March 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Luisa Iommarini, Anna Ghelli, Concetta Valentina Tropeano, Ivana Kurelac, Giulia Leone, Sara Vidoni, Anne Lombes, Massimo Zeviani, Giuseppe Gasparre, Anna Maria Porcelli
Mammalian respiratory complex I (CI) biogenesis requires both nuclear and mitochondria-encoded proteins and is mostly organized in respiratory supercomplexes. Among the CI proteins encoded by the mitochondrial DNA, NADH-ubiquinone oxidoreductase chain 1 (ND1) is a core subunit, evolutionary conserved from bacteria to mammals. Recently, ND1 has been recognized as a pivotal subunit in maintaining the structural and functional interaction among the hydrophilic and hydrophobic CI arms. A critical role of human ND1 both in CI biogenesis and in the dynamic organization of supercomplexes has been depicted, although the proof of concept is still missing and the critical amount of ND1 protein necessary for a proper assembly of both CI and supercomplexes is not defined...
March 7, 2018: International Journal of Molecular Sciences
Shu Zhou, Pontus Pettersson, Jingjing Huang, Johannes Sjöholm, Dan Sjöstrand, Régis Pomès, Martin Högbom, Peter Brzezinski, Lena Mäler, Pia Ädelroth
The Saccharomyces cerevisiae respiratory supercomplex factor 1 (Rcf1) protein is located in the mitochondrial inner membrane where it is involved in formation of supercomplexes composed of respiratory complexes III and IV. We report the solution structure of Rcf1, which forms a dimer in dodecylphosphocholine (DPC) micelles, where each monomer consists of a bundle of five transmembrane (TM) helices and a short flexible soluble helix (SH). Three TM helices are unusually charged and provide the dimerization interface consisting of 10 putative salt bridges, defining a "charge zipper" motif...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Niya Gowthami, B Sunitha, Manish Kumar, T S Keshava Prasad, N Gayathri, B Padmanabhan, M M Srinivas Bharath
In eukaryotes, mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to oxidative phosphorylation (OXPHOS). Mammalian CI is a 45 subunit complex that forms supercomplexes with other OXPHOS complexes. Since CI defects are associated with aging and neurodegeneration, it is pertinent to understand its structure-function relationship. Although genetic mutations could lower CI activity causing mitochondrial dysfunction in several pathologies, post-translational modifications (PTMs) have emerged as a key mechanism contributing to altered CI activity...
February 27, 2018: Journal of Chemical Neuroanatomy
Amanda Bundgaard, Andrew M James, William Joyce, Michael P Murphy, Angela Fago
Freshwater turtles ( Trachemys scripta ) are among the very few vertebrates capable of tolerating severe hypoxia and reoxygenation without suffering from damage to the heart. As myocardial ischemia and reperfusion causes a burst of mitochondrial reactive oxygen species (ROS) in mammals, the question arises as to whether, and if so how, this ROS burst is prevented in the turtle heart. We find here that heart mitochondria isolated from turtles acclimated to anoxia produce less ROS than mitochondria from normoxic turtles when consuming succinate...
March 1, 2018: Journal of Experimental Biology
Aldo E García-Guerrero, Yolanda Camacho-Villasana, Angélica Zamudio-Ochoa, Dennis R Winge, Xochitl Pérez-Martínez
Cytochrome b (Cyt b ) is the only mitochondrial encoded subunit from the bc 1 complex. Cbp3 and Cbp6 are chaperones necessary for translation of the COB mRNA, and Cyt b hemylation. Here we demonstrate that their role on translation is dispensable in some laboratory strains, while their role on Cyt b hemylation seems to be universally conserved. BY4742 yeast requires Cbp3 and Cbp6 for efficient COB mRNA translation, while the D273-10b strain synthesizes Cyt b at wild-type levels in the absence of Cbp3 and Cbp6...
February 23, 2018: Journal of Biological Chemistry
Joana S Sousa, Edoardo D'Imprima, Janet Vonck
Mitochondria are the power stations of the eukaryotic cell, using the energy released by the oxidation of glucose and other sugars to produce ATP. Electrons are transferred from NADH, produced in the citric acid cycle in the mitochondrial matrix, to oxygen by a series of large protein complexes in the inner mitochondrial membrane, which create a transmembrane electrochemical gradient by pumping protons across the membrane. The flow of protons back into the matrix via a proton channel in the ATP synthase leads to conformational changes in the nucleotide binding pockets and the formation of ATP...
2018: Sub-cellular Biochemistry
Lena Böttinger, Christoph U Mårtensson, Jiyao Song, Nicole Zufall, Nils Wiedemann, Thomas Becker
Mitochondria are the powerhouses of eukaryotic cells. The activity of the respiratory chain complexes generates a proton gradient across the inner membrane, which is used by the F1FO-ATP synthase to produce ATP for cellular metabolism. In baker's yeast Saccharomyces cerevisiae the cytochrome bc1 complex (complex III) and cytochrome c oxidase (complex IV) associate in respiratory chain supercomplexes. Iron-sulfur clusters (ISC) form reactive centers of respiratory chain complexes. The assembly of ISC occurs in the mitochondrial matrix and is essential for cell viability...
January 31, 2018: Molecular Biology of the Cell
Karina Salvador-Severo, Leopoldo Gómez-Caudillo, Héctor Quezada, José de Jesús García-Trejo, Alan Cárdenas-Conejo, Martha Elisa Vázquez-Memije, Fernando Minauro-Sanmiguel
BACKGROUND: Mitochondriopathies are multisystem diseases affecting the oxidative phosphorylation (OXPHOS) system. Skin fibroblasts are a good model for the study of these diseases. Fibroblasts with a complex IV mitochondriopathy were used to determine the molecular mechanism and the main affected functions in this disease. METHODS: Skin fibroblast were grown to assure disease phenotype. Mitochondria were isolated from these cells and their proteome extracted for protein identification...
May 2017: Boletín Médico del Hospital Infantil de México
Hong Koh, Gun-Seok Park, Sun-Mi Shin, Chang Eon Park, Seung Kim, Seok Joo Han, Huy Quang Pham, Jae-Ho Shin, Dong-Woo Lee
Biliary atresia (BA) results in severe bile blockage and is caused by the absence of extrahepatic ducts. Even after successful hepatic portoenterostomy, a considerable number of patients are likely to show progressive deterioration in liver function. Recent studies show that mutations in protein-coding mitochondrial DNA (mtDNA) genes and/or mitochondrial genes in nuclear DNA (nDNA) are associated with hepatocellular dysfunction. This observation led us to investigate whether hepatic dysfunctions in BA is genetically associated with mtDNA mutations...
January 17, 2018: Scientific Reports
Luis A Sánchez, Mauricio Gomez-Gallardo, Alma L Díaz-Pérez, Christian Cortes-Rojo, Jesús Campos-García
The [Fe-S] late-acting subsystem comprised of Isa1p/Isa2p, Grx5p, and Iba57p proteins (Fe-S-IBG subsystem) is involved in [4Fe-4S]-cluster protein assembly. The effect of deleting IBA57 in Saccharomyces cerevisiae on mitochondrial respiratory complex integration and functionality associated with Rieske protein maturation was evaluated. The iba57Δ mutant showed decreased expression and maturation of the Rieske protein. The loss of Rieske protein caused by IBA57 deletion affected the structure of supercomplexes III2IV2 and III2IV1 and their integration into the mitochondria, causing dysfunction in the electron transport chain...
January 14, 2018: Mitochondrion
Sze Chern Lim, Makiko Tajika, Masaru Shimura, Kirstyn T Carey, David A Stroud, Kei Murayama, Akira Ohtake, Matthew McKenzie
Medium-chain acyl-Coenzyme A dehydrogenase (MCAD) is involved in the initial step of mitochondrial fatty acid β-oxidation (FAO). Loss of function results in MCAD deficiency, a disorder that usually presents in childhood with hypoketotic hypoglycemia, vomiting and lethargy. While the disruption of mitochondrial fatty acid metabolism is the primary metabolic defect, secondary defects in mitochondrial oxidative phosphorylation (OXPHOS) may also contribute to disease pathogenesis. Therefore, we examined OXPHOS activity and stability in MCAD-deficient patient fibroblasts that have no detectable MCAD protein...
January 9, 2018: Scientific Reports
Shu Zhou, Pontus Pettersson, Peter Brzezinski, Pia Ädelroth, Lena Mäler
The Saccharomyces (S.) cerevisiae mitochondrial respiratory supercomplex factor 2 (Rcf2) plays a role in assembly of supercomplexes composed of cytochrome bc1 (complex III) and cytochrome c oxidase (complex IV). The Rcf2 protein was here expressed in E. coli, refolded and reconstituted into dodecylphosphocholine (DPC) micelles. The structural properties of Rcf2 were studied by solution NMR and near complete backbone assignment of Rcf2 was achieved. The secondary structure of Rcf2 contains seven helices, of which five are putative transmembrane (TM) helices, including, unexpectedly, a region formed by a charged 20-residue helix at the C-terminus...
December 14, 2017: Chembiochem: a European Journal of Chemical Biology
Lucía Barbier-Torres, Paula Iruzubieta, David Fernández-Ramos, Teresa C Delgado, Daniel Taibo, Virginia Guitiérrez-de-Juan, Marta Varela-Rey, Mikel Azkargorta, Nicolas Navasa, Pablo Fernández-Tussy, Imanol Zubiete-Franco, Jorge Simon, Fernando Lopitz-Otsoa, Sofia Lachiondo-Ortega, Javier Crespo, Steven Masson, Misti Vanette McCain, Erica Villa, Helen Reeves, Felix Elortza, Maria Isabel Lucena, Maria Isabel Hernández-Alvarez, Antonio Zorzano, Raúl J Andrade, Shelly C Lu, José M Mato, Juan Anguita, Mercedes Rincón, María Luz Martínez-Chantar
Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS...
December 12, 2017: Nature Communications
Fan Liu, Philip Lössl, Beverley M Rabbitts, Robert S Balaban, Albert J R Heck
Mitochondria exert an immense amount of cytophysiological functions, but the structural basis of most of these processes is still poorly understood. Here we use cross-linking mass spectrometry to probe the organization of proteins in native mouse heart mitochondria. Our approach provides the largest survey of mitochondrial protein interactions reported so far. In total, we identify 3,322 unique residue-to-residue contacts involving half of the mitochondrial proteome detected by bottom-up proteomics. The obtained mitochondrial protein interactome gives insights in the architecture and submitochondrial localization of defined protein assemblies, and reveals the mitochondrial localization of four proteins not yet included in the MitoCarta database...
February 2018: Molecular & Cellular Proteomics: MCP
Satoru Shimada, Marika Oosaki, Ryoko Takahashi, Shigefumi Uene, Sachiko Yanagisawa, Tomitake Tsukihara, Kyoko Shinzawa-Itoh
Large assemblies of respiratory chain complexes, known as supercomplexes, are present in the mitochondrial membrane in mammals and yeast, as well as in some bacterial membranes. The formation of supercomplexes is thought to contribute to efficient electron transfer, stabilization of each enzyme complex, and inhibition of reactive oxygen species (ROS) generation. In this study, mitochondria from various organisms were solubilized with digitonin, and then the solubilized complexes were separated by blue native PAGE (BN-PAGE)...
February 2018: Biochimica et Biophysica Acta
E Madison Sullivan, Edward Ross Pennington, Genevieve C Sparagna, Maria J Torres, P Darrell Neufer, Mitchel Harris, James Washington, Ethan J Anderson, Tonya N Zeczycki, David A Brown, Saame Raza Shaikh
Cardiac mitochondrial phospholipid acyl chains regulate respiratory enzymatic activity. In several diseases, the rodent cardiac phospholipidome is extensively rearranged; however, whether specific acyl chains impair respiratory enzyme function is unknown. One unique remodeling event in the myocardium of obese and diabetic rodents is an increase in docosahexaenoic acid (DHA) levels. Here, we first confirmed that cardiac DHA levels are elevated in diabetic humans relative to controls. We then used dietary supplementation of a Western diet with DHA as a tool to promote cardiac acyl chain remodeling and to study its influence on respiratory enzyme function...
January 12, 2018: Journal of Biological Chemistry
Srinivasan V Narayanan, Kunjan R Dave, Miguel A Perez-Pinzon
Induction of ischemic preconditioning (IPC) represents a potential therapy against cerebral ischemia by activation of adaptive pathways and modulation of mitochondria to induce ischemic tolerance to various cells and tissues. Mitochondrial dysfunction has been ascribed to contribute to numerous neurodegenerative conditions and cerebral ischemia. Nuclear erythroid 2-related factor 2 (Nrf2) is a transcription factor that has traditionally been involved in upregulating cellular antioxidant systems to combat oxidative stress in the brain; however, the association of Nrf2 with mitochondria in the brain remains unclear...
November 4, 2017: Translational Stroke Research
Writoban Basu Ball, John K Neff, Vishal M Gohil
Mitochondrial structure and function are influenced by the unique phospholipid composition of its membranes. While mitochondria contain all the major classes of phospholipids, recent studies have highlighted specific roles of the non-bilayer forming phospholipids phosphatidylethanolamine (PE) and cardiolipin (CL) in the assembly and activity of mitochondrial respiratory chain (MRC) complexes. The non-bilayer phospholipids are cone-shaped molecules that introduce curvature stress in the bilayer membrane and have been shown to impact mitochondrial fusion and fission...
October 25, 2017: FEBS Letters
Trevor Carden, Bhupendra Singh, Ved Mooga, Prachi Bajpai, Keshav K Singh
The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line...
December 15, 2017: Journal of Biological Chemistry
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