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Mitochondrial supercomplexes

Jennifer Senkler, Nils Rugen, Holger Eubel, Jan Hegermann, Hans-Peter Braun
The mitochondrial oxidative phosphorylation (OXPHOS) system, which is based on the presence of five protein complexes, is in the very center of cellular ATP production. Complexes I to IV are components of the respiratory electron transport chain that drives proton translocation across the inner mitochondrial membrane. The resulting proton gradient is used by complex V (the ATP synthase complex) for the phosphorylation of ADP. Occurrence of complexes I to V is highly conserved in eukaryotes, with exceptions being restricted to unicellular parasites that take up energy-rich compounds from their hosts...
April 27, 2018: Current Biology: CB
Oluwaseun B Ogunbona, Matthew G Baile, Steven M Claypool
How the absence of the major mitochondrial ADP/ATP carrier in yeast, Aac2p, results in a specific defect in cytochrome c oxidase (COX; complex IV) activity is a long-standing mystery. Aac2p physically associates with respiratory supercomplexes, which include complex IV, raising the possibility that its activity is dependent on its association with Aac2p. Here, we have leveraged a transport-dead pathogenic AAC2 point mutant to determine the basis for the reduced COX activity in the absence of Aac2p. The steady state levels of complex IV subunits encoded by the mitochondrial genome are significantly reduced in the absence of Aac2p function, whether its association with respiratory supercomplexes is preserved or not...
April 24, 2018: Molecular Biology of the Cell
María Alejandra Sánchez-Muñoz, Mónica Andrea Valdez-Solana, Mara Ibeth Campos-Almazán, Óscar Flores-Herrera, Mercedes Esparza-Perusquía, Sofia Olvera-Sánchez, Guadalupe García-Arenas, Claudia Avitia-Domínguez, Alfredo Téllez-Valencia, Erick Sierra-Campos
The increasing prevalence of diabetes continues to be a major health issue worldwide. Alteration of mitochondrial electron transport chain is a recognized hallmark of the diabetic-associated decline in liver bioenergetics; however, the molecular events involved are only poorly understood. Moringa oleifera is used for the treatment of diabetes. However, its role on mitochondrial functionality is not yet established. This study was aimed to evaluate the effect of M. oleifera extract on supercomplex formation, ATPase activity, ROS production, GSH levels, lipid peroxidation, and protein carbonylation...
2018: Biochemistry Research International
Runyu Guo, Jinke Gu, Shuai Zong, Meng Wu, Maojun Yang
Respiration is one of the most vital and basic features of living organisms. In mammals, respiration is accomplished by respiratory chain complexes located on the mitochondrial inner membrane. In the past century, scientists put tremendous efforts in understanding these complexes, but failed to solve the high resolution structure until recently. In 2016, three research groups reported the structure of respiratory chain supercomplex from different species, and fortunately the structure solved by our group has the highest resolution...
February 2018: Biomedical Journal
Kapuganti Jagadis Gupta, Aprajita Kumari, Igor Florez-Sarasa, Alisdair R Fernie, Abir U Igamberdiev
Mitochondria are not only major sites for energy production but also participate in several alternative functions, among these generation of nitric oxide (NO) and its different impacts on this organelle is increasing attention. The inner mitochondrial membrane contains the chain of protein complexes, and electron transfer via oxidation of various organic acids and reducing equivalents leads to generation of proton gradient that results in energy production. Recent evidence suggests that these complexes are sources and targets for NO...
March 24, 2018: Journal of Experimental Botany
Edgard M Mejia, Hana Zegallai, Eric D Bouchard, Versha Banerji, Amir Ravandi, Grant M Hatch
The mitochondrial polyglycerophospholipid cardiolipin (CL) is remodeled to obtain specific fatty acyl chains. This is predominantly accomplished by the transacylase enzyme tafazzin (TAZ). Barth Syndrome (BTHS) patients with TAZ gene mutations exhibit impaired TAZ activity and loss in mitochondrial respiratory function. Previous studies identified monolysocardiolipin acyltransferase-1 (MLCL AT-1) as a mitochondrial enzyme capable of remodelling CL with fatty acid. In this study, we analyzed what relationship, if any, exits between TAZ and MLCL AT-1 with regard to CL remodeling and if transfection of BTHS lymphoblasts with a MLCL AT-1 expression construct improves mitochondrial respiratory function...
March 21, 2018: Journal of Biological Chemistry
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 20, 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 20, 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 re-oxygenation 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 that heart mitochondria isolated from turtles acclimated to anoxia produce less ROS than mitochondria from normoxic turtles when consuming succinate...
April 25, 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 in translation is dispensable in some laboratory strains, whereas their role in Cyt b hemylation seems to be universally conserved. BY4742 yeast requires Cbp3 and Cbp6 for efficient COB mRNA translation, whereas the D273-10b strain synthesizes Cyt b at wildtype levels in the absence of Cbp3 and Cbp6...
April 13, 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 F1 FO -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 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). We expressed the Rcf2 protein in Escherichia coli, refolded it, and reconstituted it 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...
March 2, 2018: 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
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