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  • 1.
    Andréasson, Claes
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Mitochondria orchestrate proteostatic and metabolic stress responses2019Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, artikkel-id e47865Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The eukaryotic cell is morphologically and functionally organized as an interconnected network of organelles that responds to stress and aging. Organelles communicate via dedicated signal transduction pathways and the transfer of information in form of metabolites and energy levels. Recent data suggest that the communication between organellar proteostasis systems is a cornerstone of cellular stress responses in eukaryotic cells. Here, we discuss the integration of proteostasis and energy fluxes in the regulation of cellular stress and aging. We emphasize the molecular architecture of the regulatory transcriptional pathways that both sense and control metabolism and proteostasis. A special focus is placed on mechanistic insights gained from the model organism budding yeast in signaling from mitochondria to the nucleus and how this shapes cellular fitness.

  • 2. Bareth, Bettina
    et al.
    Nikolov, Miroslav
    Lorenzi, Isotta
    Hildenbeutel, Markus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mick, David U.
    Helbig, Christin
    Urlaub, Henning
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rehling, Peter
    Dennerlein, Sven
    Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox12016Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, nr 10, s. 1570-1580Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial cytochrome c oxidase assembles in the inner membrane from subunits of dual genetic origin. The assembly process of the enzyme is initiated by membrane insertion of the mitochondria-encoded Cox1 subunit. During complex maturation, transient assembly intermediates, consisting of structural subunits and specialized chaperone-like assembly factors, are formed. In addition, cofactors such as heme and copper have to be inserted into the nascent complex. To regulate the assembly process, the availability of Cox1 is under control of a regulatory feedback cycle in which translation of COX1 mRNA is stalled when assembly intermediates of Cox1 accumulate through inactivation of the translational activator Mss51. Here we isolate a cytochrome c oxidase assembly intermediate in preparatory scale from coa1 Delta. mutant cells, using Mss51 as bait. We demonstrate that at this stage of assembly, the complex has not yet incorporated the heme a cofactors. Using quantitative mass spectrometry, we define the protein composition of the assembly intermediate and unexpectedly identify the putative methyltransferase Oms1 as a constituent. Our analyses show that Oms1 participates in cytochrome c oxidase assembly by stabilizing newly synthesized Cox1.

  • 3. Bauerschmitt, Heike
    et al.
    Mick, David
    Deckers, Markus
    Vollmer, C
    Funes, S
    Kehrein, Kirsten
    University of Kaiserslautern, Germany.
    Ott, Martin
    University of Kaiserslautern, Germany.
    Rehling, Peter
    Herrmann, Johannes
    Ribosome-binding proteins Mdm38 and Mba1 display overlapping functions for regulation of mitochondrial translation2010Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 21, nr 12, s. 1937-1944Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Biogenesis of respiratory chain complexes depends on the expression of mitochondrial-encoded subunits. Their synthesis occurs on membrane-associated ribosomes and is probably coupled to their membrane insertion. Defects in expression of mitochondrial translation products are among the major causes of mitochondrial disorders. Mdm38 is related to Letm1, a protein affected in Wolf-Hirschhorn syndrome patients. Like Mba1 and Oxa1, Mdm38 is an inner membrane protein that interacts with ribosomes and is involved in respiratory chain biogenesis. We find that simultaneous loss of Mba1 and Mdm38 causes severe synthetic defects in the biogenesis of cytochrome reductase and cytochrome oxidase. These defects are not due to a compromised membrane binding of ribosomes but the consequence of a mis-regulation in the synthesis of Cox1 and cytochrome b. Cox1 expression is restored by replacing Cox1-specific regulatory regions in the mRNA. We conclude, that Mdm38 and Mba1 exhibit overlapping regulatory functions in translation of selected mitochondrial mRNAs.

  • 4.
    Björck, Markus L.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zhou, Shu
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rydström Lundin, Camilla
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Reaction of S-cerevisiae mitochondria with ligands: Kinetics of CO and O-2 binding to flavohemoglobin and cytochrome c oxidase2017Inngår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1858, nr 2, s. 182-188Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kinetic methods used to investigate electron and proton transfer within cytochrome c oxidase (CytcO) are often based on the use of light to dissociate small ligands, such as CO, thereby initiating the reaction. Studies of intact mitochondria using these methods require identification of proteins that may bind CO and determination of the ligand-binding kinetics. In the present study we have investigated the kinetics of CO-ligand binding to S. cerevisiae mitochondria and cellular extracts. The data indicate that CO binds to two proteins, CytcO and a (yeast) flavohemoglobin (yHb). The latter has been shown previously to reside in both the cell cytosol and the mitochondrial matrix. Here, we found that yHb resides also in the intermembrane space and binds CO in its reduced state. As observed previously, we found that the yHb population in the mitochondrial matrix binds CO, but only after removal of the inner membrane. The mitochondrial yHb (in both the intermembrane space and the matrix) recombines with CO with T congruent to 270 ms, which is significantly slower than observed with the cytosolic yHb (main component T congruent to 1.3 ms). The data indicate that the yHb populations in the different cell compartments differ in structure.

  • 5.
    Dawitz, Hannah
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Schäfer, Jacob
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Schaart, Judith Maria
    Magits, Wout
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rcf1 modulates cytochrome c oxidase activity especially under energy-demanding conditionsManuskript (preprint) (Annet vitenskapelig)
  • 6. Forsberg, Jeremy
    et al.
    Li, Xinge
    Akpinar, Birce
    Salvatori, Roger
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Zhivotovsky, Boris
    Olsson, Magnus
    A caspase-2-RFXANK interaction and its implication for MHC class II expression2018Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 9, artikkel-id 80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite recent achievements implicating caspase-2 in tumor suppression, the enzyme stands out from the apoptotic caspase family as a factor whose function requires further clarification. To specify enzyme characteristics through the definition of interacting proteins in apoptotic or non-apoptotic settings, a yeast 2-hybrid (Y2H) screen was performed using the full-length protein as bait. The current report describes the analysis of a captured prey and putative novel caspase-2 interacting factor, the regulatory factor X-associated ankyrin-containing protein (RFXANK), previously associated with CIITA, the transactivator regulating cell-type specificity and inducibility of MHC class II gene expression. The interaction between caspase-2 and RFXANK was verified by co-immunoprecipitations using both exogenous and endogenous proteins, where the latter approach suggested that binding of the components occurs in the cytoplasm. Cellular co-localization was confirmed by transfection of fluorescently conjugated proteins. Enhanced caspase-2 processing in RFXANK-overexpressing HEK293T cells treated with chemotherapeutic agents further supported Y2H data. Yet, no distinct differences with respect to MHC class II expression were observed in plasma membranes of antigen-presenting cells derived from wild type and caspase-2(-/-) mice. In contrast, increased levels of the total MHC class II protein was evident in protein lysates from caspase-2 RNAi-silenced leukemia cell lines and B-cells isolated from gene-targeted mice. Together, these data identify a novel caspase-2-interacting factor, RFXANK, and indicate a potential non-apoptotic role for the enzyme in the control of MHC class II gene regulation.

  • 7.
    Gruschke, Steffi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kehrein, Kirsten
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roempler, Katharina
    Groene, Kerstin
    Israel, Lars
    Imhof, Axel
    Herrmann, Johannes M.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly2011Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 193, nr 6, s. 1101-1114Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondria contain their own genetic system to express a small number of hydrophobic polypeptides, including cytochrome b, an essential subunit of the bc(1) complex of the respiratory chain. In this paper, we show in yeast that Cbp3, a bc(1) complex assembly factor, and Cbp6, a regulator of cytochrome b translation, form a complex that associates with the polypeptide tunnel exit of mitochondrial ribosomes and that exhibits two important functions in the biogenesis of cytochrome b. On the one hand, the interaction of Cbp3 and Cbp6 with mitochondrial ribosomes is necessary for efficient translation of cytochrome b messenger ribonucleic acid or transcript. On the other hand, the Cbp3-Cbp6 complex interacts directly with newly synthesized cytochrome b in an assembly intermediate that is not ribosome bound and that contains the assembly factor Cbp4. Our results suggest that synthesis of cytochrome b occurs preferentially on those ribosomes that have the Cbp3-Cbp6 complex bound to their tunnel exit, an arrangement that may ensure tight coordination of cytochrome b synthesis and assembly.

  • 8.
    Gruschke, Steffi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Römpler, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hildenbeutel, Markus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kehrein, Kirsten
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kuehl, Inge
    Bonnefoy, Nathalie
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The Cbp3-Cbp6 complex coordinates cytochrome b synthesis with bc(1) complex assembly in yeast mitochondria2012Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 199, nr 1, s. 137-150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Respiratory chain complexes in mitochondria are assembled from subunits derived from two genetic systems. For example, the bc1 complex consists of nine nuclear encoded subunits and the mitochondrially encoded subunit cytochrome b. We recently showed that the Cbp3-Cbp6 complex has a dual function for biogenesis of cytochrome b: it is both required for efficient synthesis of cytochrome b and for protection of the newly synthesized protein from proteolysis. Here, we report that Cbp3-Cbp6 also coordinates cytochrome b synthesis with bc1 complex assembly. We show that newly synthesized cytochrome b assembled through a series of four assembly intermediates. Blocking assembly at early and intermediate steps resulted in sequestration of Cbp3-Cbp6 in a cytochrome b-containing complex, thereby making Cbp3-Cbp6 unavailable for cytochrome b synthesis and thus reducing overall cytochrome b levels. This feedback loop regulates protein synthesis at the inner mitochondrial membrane by directly monitoring the efficiency of bc1 complex assembly.

  • 9.
    Heublein, Manfred
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Burguillos, Miguel A.
    Vögtle, F. Nora
    Teixeira, Pedro F.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Imhof, Axel
    Meisinger, Chris
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The novel component Kgd4 recruits the E3 subunit to the mitochondrial alpha-ketoglutarate dehydrogenase2014Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, nr 21, s. 3342-3349Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial citric acid cycle is a central hub of cellular metabolism, providing intermediates for biosynthetic pathways and channeling electrons to the respiratory chain complexes. In this study, we elucidated the composition and organization of the multienzyme complex alpha-ketoglutarate dehydrogenase (alpha-KGDH). In addition to the three classical E1-E3 subunits, we identified a novel component, Kgd4 (Ymr31/MRPS36), which was previously assigned to be a subunit of the mitochondrial ribosome. Biochemical analyses demonstrate that this protein plays an evolutionarily conserved role in the organization of mitochondrial alpha-KGDH complexes of fungi and animals. By binding to both the E1-E2 core and the E3 subunit, Kgd4 acts as a molecular adaptor that is necessary to a form a stable alpha-KGDH enzyme complex. Our work thus reveals a novel subunit of a key citric acid-cycle enzyme and shows how this large complex is organized.

  • 10.
    Heublein, Manfred
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Burguillos, Miguel
    Vögtle, Nora
    Teixeira, Pedro
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Imhof, Axel
    Meisinger, Chris
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The novel component Kgd4 recruits the E3 subunit to the mitochondrial α-ketoglutarate dehydrogenaseManuskript (preprint) (Annet vitenskapelig)
  • 11.
    Heublein, Manfred
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ndi, Mama
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vazquez-Calvo, Carmela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vögtle, F.-Nora
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Alternative Translation Initiation at a UUG Codon Gives Rise to Two Functional Variants of the Mitochondria! Protein Kgd42019Inngår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 431, nr 7, s. 1460-1467Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kgd4 is a novel subunit of the mitochondria! a-ketoglutarate dehydrogenase complex (KGDH). In yeast, the protein is present in two forms of unknown origin, as there is only one open reading frame and no alternative splicing. Here, we show that the two forms of Kgd4 derive from one mRNA that is translated by employing two alternative start sites. The standard, annotated AUG codon gives rise to the short form of the protein, while an upstream UUG codon is utilized to generate the larger form. However, both forms can be efficiently imported into mitochondria and stably incorporate into KGDH to support its activity. Translation of the long variant depends on sequences directly upstream of the alternative initiation site, demonstrating that translation initiation and its efficiency are dictated by the sequence context surrounding a specific codon. In summary, the two forms of Kgd4 follow a very unusual biogenesis pathway, supporting the notion that translation initiation in yeast is more flexible than it is widely recognized.

  • 12.
    Heublein, Manfred
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    KGDH membrane association, purification and structureManuskript (preprint) (Annet vitenskapelig)
  • 13.
    Heublein, Manfred
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vögtle, Nora
    Meisinger, Chris
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Alternative initiation at a UUG codon gives rise to two functional variants of the mitochondrial protein Kgd4Manuskript (preprint) (Annet vitenskapelig)
  • 14.
    Hildenbeutel, Markus
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hegg, Eric L.
    Gruschke, Steffi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meunier, Brigitte
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The timing of heme incorporation into yeast cytochrome bManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    During oxidative phosphorylation electrons are transferred from NADH and succinate to the final electron acceptor oxygen by the complexes of the respiratory chain. These complexes carry redox active prosthetic groups that allow the transfer of electrons. Cytochrome b of the bc1 complex is encoded in the mitochondrial genome and acquires two heme b cofactors during its biogenesis. In this work we aimed to understand the mechanism and timing of cytochrome b hemylation. We provide evidence that cytochrome b present in the first bc1 complex assembly intermediate that contains the assembly factors Cbp3-Cbp6 and Cbp4 carries heme. This demonstrates that heme acquisition occurs very early during cytochrome b biogenesis. Moreover, by analyzing cytochrome b mutants lacking either of the two heme moieties, we reveal an obligate order of heme insertion into cytochrome b and suggest an incorporation mode from the intermembrane space. We propose a model in which Cbp3-Cbp6 keeps cytochrome b in a conformation allowing heme acquisition. Upon heme insertion, cytochrome b most likely undergoes a conformational change that enables binding of Cbp4, a pre-requisite for further assembly. Cbp4 thus might exhibit a proofreading function in hemylation.

  • 15.
    Hildenbeutel, Markus
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hegg, Eric L.
    Stephan, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gruschke, Steffi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meunier, Brigitte
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondria! translation2014Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 205, nr 4, s. 511-524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial respiratory chain complexes convert chemical energy into a membrane potential by connecting electron transport with charge separation. Electron transport relies on redox cofactors that occupy strategic positions in the complexes. How these redox cofactors are assembled into the complexes is not known. Cytochrome b, a central catalytic subunit of complex III, contains two henne bs. Here, we unravel the sequence of events in the mitochondrial inner membrane by which cytochrome b is hemylated. Heme incorporation occurs in a strict sequential process that involves interactions of the newly synthesized cytochrome b with assembly factors and structural complex III subunits. These interactions are functionally connected to cofactor acquisition that triggers the progression of cytochrome b through successive assembly intermediates. Failure to hemylate cytochrome b sequesters the Cbp3-Cbp6 complex in early assembly intermediates, thereby causing a reduction in cytochrome b synthesis via a feedback loop that senses hemylation of cytochrome b.

  • 16.
    Kehrein, Kirsten
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Bonnefoy, Nathalie
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mitochondrial Protein Synthesis: Efficiency and Accuracy2013Inngår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 19, nr 16, s. 1928-1939Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Significance: The mitochondrial genetic system is responsible for the production of a few core-subunits of the respiratory chain and ATP synthase, the membrane protein complexes driving oxidative phosphorylation (OXPHOS). Efficiency and accuracy of mitochondrial protein synthesis determines how efficiently new OXPHOS complexes can be made. Recent Advances: The system responsible for expression of the mitochondrial-encoded subunits developed from that of the bacterial ancestor of mitochondria. Importantly, many aspects of genome organization, transcription, and translation have diverged during evolution. Recent research has provided new insights into the architecture, regulation, and organelle-specific features of mitochondrial translation. Mitochondrial ribosomes contain a number of proteins absent from prokaryotic ribosomes, implying that in mitochondria, ribosomes were tailored to fit the requirements of the organelle. In addition, mitochondrial gene expression is regulated post-transcriptionally by a number of mRNA-specific translational activators. At least in yeast, these factors can regulate translation in respect to OXPHOS complex assembly to adjust the level of newly synthesized proteins to amounts that can be successfully assembled into respiratory chain complexes. Critical Issues: Mitochondrial gene expression is determining aging in eukaryotes, and a number of recent reports indicate that efficiency of translation directly influences this process. Future Directions: Here we will summarize recent advances in our understanding of mitochondrial protein synthesis by comparing the knowledge acquired in the systems most commonly used to study mitochondrial biogenesis. However, many steps have not been understood mechanistically. Innovative biochemical and genetic approaches have to be elaborated to shed light on these important processes. Antioxid. Redox Signal. 19, 1928-1939.

  • 17.
    Kehrein, Kirsten
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Conserved and Organelle-Specific Molecular Mechanisms of Translation in Mitochondria2012Inngår i: Organelle Genetics: Evolution of Organelle Genomes and Gene Expression, New York: Springer, 2012, s. 401-429Kapittel i bok, del av antologi (Fagfellevurdert)
  • 18.
    Kehrein, Kirsten
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Schilling, Ramon
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vargas Möller-Hergt, Braulio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wurm, Christian A.
    Jakobs, Stefan
    Lamkemeyer, Tobias
    Langer, Thomas
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Organization of Mitochondrial Gene Expression in Two Distinct Ribosome-Containing Assemblies2015Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, nr 6, s. 843-853Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondria contain their own genetic system that provides subunits of the complexes driving oxidative phosphorylation. A quarter of the mitochondrial proteome participates in gene expression, but how all these factors are orchestrated and spatially organized is currently unknown. Here, we established a method to purify and analyze native and intact complexes of mitochondrial ribosomes. Quantitative mass spectrometry revealed extensive interactions of ribosomes with factors involved in all the steps of posttranscriptional gene expression. These interactions result in large expressosome-like assemblies that we termed mitochondrial organization of gene expression (MIOREX) complexes. Superresolution microscopy revealed that most MIOREX complexes are evenly distributed throughout the mitochondrial network, whereas a subset is present as nucleoid-MIOREX complexes that unite the whole spectrum of organellar gene expression. Our work therefore provides a conceptual framework for the spatial organization of mitochondrial protein synthesis that likely developed to facilitate gene expression in the organelle.

  • 19. Kuzmenko, Anton
    et al.
    Derbikova, Ksenia
    Salvatori, Roger
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Tankov, Stoyan
    Atkinson, Gemma C.
    Tenson, Tanel
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kamenski, Piotr
    Hauryliuk, Vasili
    Aim-less translation: loss of Saccharomyces cerevisiae mitochondrial translation initiation factor mIF3/Aim23 leads to unbalanced protein synthesis2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 18749Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial genome almost exclusively encodes a handful of transmembrane constituents of the oxidative phosphorylation (OXPHOS) system. Coordinated expression of these genes ensures the correct stoichiometry of the system's components. Translation initiation in mitochondria is assisted by two general initiation factors mIF2 and mIF3, orthologues of which in bacteria are indispensible for protein synthesis and viability. mIF3 was thought to be absent in Saccharomyces cerevisiae until we recently identified mitochondrial protein Aim23 as the missing orthologue. Here we show that, surprisingly, loss of mIF3/Aim23 in S. cerevisiae does not indiscriminately abrogate mitochondrial translation but rather causes an imbalance in protein production: the rate of synthesis of the Atp9 subunit of F1F0 ATP synthase (complex V) is increased, while expression of Cox1, Cox2 and Cox3 subunits of cytochrome c oxidase (complex IV) is repressed. Our results provide one more example of deviation of mitochondrial translation from its bacterial origins.

  • 20.
    Marin-Buera, Lorena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ndi, Mama
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meunier, Brigitte
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Functional characterization of disease-causing cytochrome b mutationsManuskript (preprint) (Annet vitenskapelig)
  • 21.
    Mata Forsberg, Manuel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Björkander, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pang, Yanhong
    Lundqvist, Ludwig
    Ndi, Mama
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Escribá, Irene Buesa
    Jaeger, Marie-Charlotte
    Roos, Stefan
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Extracellular membrane vesicles from lactobacilli dampen IFN-γ responses in a monocyte-dependent mannerInngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Artikkel i tidsskrift (Fagfellevurdert)
  • 22.
    Ndi, Mama
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Marin-Buera, Lorena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Salvatori, Roger
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Singh, Abeer Prakash
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Biogenesis of the bc(1) Complex of the Mitochondria! Respiratory Chain2018Inngår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, nr 21, s. 3892-3905Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The oxidative phosphorylation system contains four respiratory chain complexes that connect the transport of electrons to oxygen with the establishment of an electrochemical gradient over the inner membrane for ATP synthesis. Due to the dual genetic source of the respiratory chain subunits, its assembly requires a tight coordination between nuclear and mitochondrial gene expression machineries. In addition, dedicated assembly factors support the step-by-step addition of catalytic and accessory subunits as well as the acquisition of redox cofactors. Studies in yeast have revealed the basic principles underlying the assembly pathways. In this review, we summarize work on the biogenesis of the bc(1) complex or complex III, a central component of the mitochondrial energy conversion system.

  • 23.
    Ndi, Mama
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Masuyer, Geoffrey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. University of Bath, UK.
    Dawitz, Hannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Carlström, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Michel, Mirco
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Elofsson, Arne
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Rapp, Mikaela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Stenmark, Pål
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Lund University, Sweden.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Structural basis for Cbp3 interaction with newly synthesized cytochrome b during mitochondrial respiratory chain assembly2019Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, nr 45, s. 16663-16671Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Assembly of the mitochondrial respiratory chain requires the coordinated synthesis of mitochondrial and nuclear encoded subunits, redox co-factor acquisition, and correct joining of the subunits to form functional complexes. The conserved Cbp3–Cbp6 chaperone complex binds newly synthesized cytochrome b and supports the ordered acquisition of the heme co-factors. Moreover, it functions as a translational activator by interacting with the mitoribosome. Cbp3 consists of two distinct domains, an N-terminal domain present in mitochondrial Cbp3 homologs, and a highly conserved C-terminal domain comprising a ubiquinol–cytochrome c chaperone region. Here, we solved the crystal structure of this C-terminal domain from a bacterial homolog at 1.4 Å resolution, revealing a unique all-helical fold. This structure allowed mapping of the interaction sites of yeast Cbp3 with Cbp6 and cytochrome b via site-specific photo-crosslinking. We propose that mitochondrial Cbp3 homologs carry an N-terminal extension that positions the conserved C-terminal domain at the ribosomal tunnel exit for an efficient interaction with its substrate, the newly synthesized cytochrome b protein.

  • 24.
    Ott, Martin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Amunts, Alexey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Brown, Alan
    Organization and Regulation of Mitochondrial Protein Synthesis2016Inngår i: Annual Review of Biochemistry, ISSN 0066-4154, E-ISSN 1545-4509, Vol. 85, s. 77-101Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Mitochondria are essential organelles of endosymbiotic origin that are responsible for oxidative phosphorylation within eukaryotic cells. Independent evolution between species has generated mitochondrial genomes that are extremely diverse, with the composition of the vestigial genome determining their translational requirements. Typically, translation within mitochondria is restricted to a few key subunits of the oxidative phosphorylation complexes that are synthesized by dedicated ribosomes (mitoribosomes). The dramatically rearranged mitochondrial genomes, the limited set of transcripts, and the need for the synthesized proteins to coassemble with nuclear-encoded subunits have had substantial consequences for the translation machinery. Recent high-resolution cryo-electron microscopy has revealed the effect of coevolution on the mitoribosome with the mitochondrial genome. In this review, we place the new structural information in the context of the molecular mechanisms of mitochondrial translation and focus on the novel ways protein synthesis is organized and regulated in mitochondria.

  • 25.
    Rathore, Sorbhi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berndtsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Marin-Buera, Lorena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Conrad, Julian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Carroni, Marta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Cryo-EM structure of the yeast respiratory supercomplex2019Inngår i: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 26, nr 1, s. 50-57Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Respiratory chain complexes execute energy conversion by connecting electron transport with proton translocation over the inner mitochondrial membrane to fuel ATP synthesis. Notably, these complexes form multi-enzyme assemblies known as respiratory supercomplexes. Here we used single-particle cryo-EM to determine the structures of the yeast mitochondria! respiratory supercomplexes III2IV and III2IV2, at 3.2-angstrom and 3.5-angstrom resolutions, respectively. We revealed the overall architecture of the supercomplex, which deviates from the previously determined assemblies in mammals; obtained a near-atomic structure of the yeast complex IV; and identified the protein-protein and protein-lipid interactions implicated in supercomplex formation. Take together, our results demonstrate convergent evolution of supercomplexes in mitochondria that, while building similar assemblies, results in substantially different arrangements and structural solutions to support energy conversion.

  • 26. Rehklau, K.
    et al.
    Gurniak, C. B.
    Conrad, M.
    Friauf, E.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rust, M. B.
    Adf/cofilin proteins translocate to mitochondria during apoptosis but are not generally required for cell death signaling2012Inngår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 19, nr 6, s. 958-967Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-muscle cofilin (n-cofilin) is a member of the ADF/cofilin family of actin depolymerizing proteins. Recent studies reported a mitochondrial translocation of n-cofilin during apoptosis. As these studies also revealed impaired cytochrome c release and a block in apoptosis upon small interfering RNA-mediated n-cofilin knockdown, n-cofilin was postulated to be essential for apoptosis induction. To elucidate the general importance of ADF/cofilin activity for apoptosis, we exposed mouse embryonic fibroblasts deficient for n-cofilin, ADF (actin depolymerizing factor), or all ADF/cofilin isoforms to well-characterized apoptosis inducers. Cytochrome c release, caspase-3 activation, and apoptotic chromatin condensation were unchanged in all mutant fibroblasts. Thus, we conclude that ADF/cofilin activity is not generally required for induction or progression of apoptosis in mammalian cells. Interestingly, mitochondrial association of ADF and n-cofilin during apoptosis was preceded by, and dependent on, actin that translocated by a yet unknown mechanism to mitochondria during cell death.

  • 27. Rehklau, Katharina
    et al.
    Hoffmann, Lena
    Gurniak, Christine B.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Witke, Walter
    Scorrano, Luca
    Culmsee, Carsten
    Rust, Marco B.
    Cofilin1-dependent actin dynamics control DRP1-mediated mitochondrial fission2017Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 8, artikkel-id e3063Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondria form highly dynamic networks in which organelles constantly fuse and divide. The relevance of mitochondrial dynamics is evident from its implication in various human pathologies, including cancer or neurodegenerative, endocrine and cardiovascular diseases. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission that oligomerizes at the mitochondrial outer membrane and hydrolyzes GTP to drive mitochondrial fragmentation. Previous studies demonstrated that DRP1 recruitment and mitochondrial fission is promoted by actin polymerization at the mitochondrial surface, controlled by the actin regulatory proteins inverted formin 2 (INF2) and Spire1C. These studies suggested the requirement of additional actin regulatory activities to control DRP1-mediated mitochondrial fission. Here we show that the actin-depolymerizing protein cofilin1, but not its close homolog actin-depolymerizing factor (ADF), is required to maintain mitochondrial morphology. Deletion of cofilin1 caused mitochondrial DRP1 accumulation and fragmentation, without altering mitochondrial function or other organelles' morphology. Mitochondrial morphology in cofilin1-deficient cells was restored upon (i) re-expression of wild-type cofilin1 or a constitutively active mutant, but not of an actin-binding-deficient mutant, (ii) pharmacological destabilization of actin filaments and (iii) genetic depletion of DRP1. Our work unraveled a novel function for cofilin1-dependent actin dynamics in mitochondrial fission, and identified cofilin1 as a negative regulator of mitochondrial DRP1 activity. We conclude that cofilin1 is required for local actin dynamics at mitochondria, where it may balance INF2/Spire1C-induced actin polymerization.

  • 28.
    Rydström Lundin, Camilla
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    von Ballmoos, Christoph
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Regulatory role of the respiratory supercomplex factors in Saccharomyces cerevisiae2016Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 31, s. E4476-E4485Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The respiratory supercomplex factors (Rcf) 1 and 2 mediate supramolecular interactions between mitochondrial complexes III (ubiquinolcytochrome c reductase; cyt. bc(1)) and IV (cytochrome c oxidase; CytcO). In addition, removal of these polypeptides results in decreased activity of CytcO, but not of cyt. bc(1). In the present study, we have investigated the kinetics of ligand binding, the singleturn-over reaction of CytcO with O-2, and the linked cyt. bc(1)-CytcO quinol oxidation-oxygen-reduction activities in mitochondria in which Rcf1 or Rcf2 were removed genetically (strains rcf1 Delta and rcf2 Delta, respectively). The data show that in the rcf1 Delta and rcf2 Delta strains, in a significant fraction of the population, ligand binding occurs over a time scale that is similar to 100-fold faster (tau congruent to 100 mu s) than observed with the wild-type mitochondria (tau congruent to 10 ms), indicating structural changes. This effect is specific to removal of Rcf and not dissociation of the cyt. bc(1)-CytcO supercomplex. Furthermore, in the rcf1 Delta and rcf2 Delta strains, the single-turnover reaction of CytcO with O-2 was incomplete. This observation indicates that the lower activity of CytcO is caused by a fraction of inactive CytcO rather than decreased CytcO activity of the entire population. Furthermore, the data suggest that the Rcf1 polypeptide mediates formation of an electrontransfer bridge from cyt. bc(1) to CytcO via a tightly bound cyt. c. We discuss the significance of the proposed regulatory mechanism of Rcf1 and Rcf2 in the context of supramolecular interactions between cyt. bc(1) and CytcO.

  • 29.
    Salvatori, Roger
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kehrein, Kirsten
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Singh, Abeer Prakash
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vargas Möller-Hergt, Braulio
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Aftab, Wasim
    Imhof, Axel
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Molecular wiring of a mitochondrial translation feedback loopManuskript (preprint) (Annet vitenskapelig)
  • 30.
    Schäfer, Jacob
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Dawitz, Hannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Regulation of cytochrome c oxidase activity by modulation of the catalytic site2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 11397Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The respiratory supercomplex factor 1 (Rcf 1) in Saccharomyces cerevisiae binds to intact cytochrome c oxidase (CytcO) and has also been suggested to be an assembly factor of the enzyme. Here, we isolated CytcO from rcf1Δ mitochondria using affinity chromatography and investigated reduction, inter-heme electron transfer and ligand binding to heme a3. The data show that removal of Rcf1 yields two CytcO sub-populations. One of these sub-populations exhibits the same functional behavior as CytcO isolated from the wild-type strain, which indicates that intact CytcO is assembled also without Rcf1. In the other sub-population, which was shown previously to display decreased activity and accelerated ligand-binding kinetics, the midpoint potential of the catalytic site was lowered. The lower midpoint potential allowed us to selectively reduce one of the two sub-populations of the rcf1Δ CytcO, which made it possible to investigate the functional behavior of the two CytcO forms separately. We speculate that these functional alterations reflect a mechanism that regulates O2 binding and trapping in CytcO, thereby altering energy conservation by the enzyme.

  • 31.
    Schäfer, Jacob
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Dawitz, Hannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Structural and functional heterogeneity of cytochrome c oxidase in S. cerevisiae2018Inngår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1859, nr 9, s. 699-704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Respiration in Saccharomyces cerevisiae is regulated by small proteins such as the respiratory supercomplex factors (Rcf). One of these factors (Rcf1) has been shown to interact with complexes III (cyt. bc1) and IV (cytochrome c oxidase, CytcO) of the respiratory chain and to modulate the activity of the latter. Here, we investigated the effect of deleting Rcf1 on the functionality of CytcO, purified using a protein C-tag on core subunit 1 (Cox1). Specifically, we measured the kinetics of ligand binding to the CytcO catalytic site, the O2-reduction activity and changes in light absorption spectra. We found that upon removal of Rcf1 a fraction of the CytcO is incorrectly assembled with structural changes at the catalytic site. The data indicate that Rcf1 modulates the assembly and activity of CytcO by shifting the equilibrium of structural sub-states toward the fully active, intact form.

  • 32. Stoldt, Stefan
    et al.
    Wenzel, Dirk
    Kehrein, Kirsten
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Riedel, Dietmar
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jakobs, Stefan
    Spatial orchestration of mitochondrial translation and OXPHOS complex assembly2018Inngår i: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 20, nr 5, s. 528-534Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxidative phosphorylation (OXPHOS) is vital for the regeneration of the vast majority of ATP in eukaryotic cells(1). OXPHOS is carried out by large multi-subunit protein complexes in the cristae membranes, which are invaginations of the mitochondrial inner membrane. The OXPHOS complexes are a mix of subunits encoded in the nuclear and mitochondrial genomes. Thus, the assembly of these dual-origin complexes is an enormous logistical challenge for the cell. Using super-resolution microscopy (nanoscopy) and quantitative cryo-immunogold electron microscopy, we determined where specific transcripts are translated and where distinct assembly steps of the dual-origin complexes in the yeast Saccharomyces cerevisiae occur. Our data indicate that the mitochondrially encoded proteins of complex III and complex IV are preferentially inserted in different sites of the inner membrane than those of complex V. We further demonstrate that the early, but not the late, assembly steps of complex III and complex IV occur preferentially in the inner boundary membrane. By contrast, all steps of complex V assembly occur mainly in the cristae membranes. Thus, OXPHOS complex assembly is spatially well orchestrated, probably representing an unappreciated regulatory layer in mitochondrial biogenesis.

  • 33.
    Suhm, Tamara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Habernig, Lukas
    Rzepka, Magdalena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    A novel system to monitor mitochondrial translation in yeast2018Inngår i: Microbial Cell, ISSN 2311-2638, Vol. 5, nr 3, s. 158-164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial genome is responsible for the production of a handful of polypeptides that are core subunits of the membrane-bound oxidative phosphorylation system. Until now the mechanistic studies of mitochondrial protein synthesis inside cells have been conducted with inhibition of cytoplasmic protein synthesis to reduce the background of nuclear gene expression with the undesired consequence of major disturbances of cellular signaling cascades. Here we have generated a system that allows direct monitoring of mitochondrial translation in unperturbed cells. A recoded gene for superfolder GFP was inserted into the yeast (Saccharomyces cerevisiae) mitochondrial genome and enabled the detection of translation through fluorescence microscopy and flow cytometry in functional mitochondria. This novel tool allows the investigation of the function and regulation of mitochondrial translation during stress signaling, aging and mitochondrial biogenesis.

  • 34.
    Suhm, Tamara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dawitz, Hannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Peselj, Carlotta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Masser, Anna E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hanzén, Sarah
    Ambrožič, Matevž
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Smialowska, Agata
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Björck, Markus L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinski, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Nyström, Thomas
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Andréasson, Claes
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis2018Inngår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 27, nr 6, s. 1309-1322Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cellular proteostasis ismaintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interor-ganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan.

  • 35.
    Suhm, Tamara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Different genetic approaches to mutate the mitochondrial ribosomal protein S12Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Over the last decades, an ever-growing number of tools became available to manipulate the genome of the model organism Saccharomyces cerevisiae. The most common approach to study a mutation in a protein is to first replace the native gene with a selection cassette via homologous recombination. In a second step, the mutated gene can be expressed from a plasmid. For certain applications, however, it is necessary to integrate the mutation in the genome. Here we introduced a mutated variant of the mitochondrial ribosomal protein S12 (Mrps12), a protein of the highly conserved accuracy center of the mitochondrial ribosome, using an integrative plasmid. First, we attempted to use a counter-selectable strategy by employing the uracil selection cassette (URA3) in combination with 5-fluoroorotic acid (5-FOA). We observed that this approach is not ideal for mutating certain crucial mitochondrial proteins. In our hands, this method only gave false-positive results. Most likely, deletion of MRPS12 and subsequent loss of mitochondrial DNA caused genome instability. This gave rise to mutated versions of URA3 which could no longer be used for counter selection. Therefore, we eventually introduced the MRPS12* under control of its endogenous promotor and terminator via an integrative plasmid in the deletion strain.

  • 36.
    Suhm, Tamara
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mitochondrial translation and cellular stress response2017Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 367, nr 1, s. 21-31Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Mitochondria are organelles critical for the functionality of eukaryotic cells. One of their most prominent functions is energy conversion, thereby producing most of the cellular ATP. Energy conversion relies on the oxidative phosphorylation system, an ensemble of large protein complexes that include the respiratory chain and the ATP synthase. Biogenesis of this machinery requires the coordination of two separate genetic systems, namely nuclear and mitochondrial gene expression. Recent research into the molecular causes of aging have revealed a prominent contribution of mitochondrial gene expression on many aspects of degenerative processes that typically involve cellular stress signaling pathways. In this review, we summarize recent developments in attempting to identify the molecular mechanism by which dysfunction of mitochondrial gene expression activates cellular stress signaling pathways and how this affects organismal aging. By comparing data obtained in various model organisms, we identify conserved and species-specific aspects of this mitochondria-to-nucleus signaling.

  • 37.
    Vargas Möller-Hergt, Braulio
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Carlström, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Stephan, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Imhof, Axel
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The ribosome receptors Mrx15 and Mba1 jointly organize cotranslational insertion and protein biogenesis in mitochondria2018Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 29, nr 20, s. 2359-2507Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial gene expression in Saccharomyces cerevisiae is responsible for the production of highly hydrophobic subunits of the oxidative phosphorylation system. Membrane insertion occurs cotranslationally on membrane-bound mitochondrial ribosomes. Here, by employing a systematic mass spectrometry-based approach, we discovered the previously uncharacterized membrane protein Mrx15 that interacts via a soluble C-terminal domain with the large ribosomal subunit. Mrx15 contacts mitochondrial translation products during their synthesis and plays, together with the ribosome receptor Mba1, an overlapping role in cotranslational protein insertion. Taken together, our data reveal how these ribosome receptors organize membrane protein biogenesis in mitochondria.

  • 38.
    Vargas Möller-Hergt, Braulio
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Carlström, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Suhm, Tamara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Insertion Defects of Mitochondrially Encoded Proteins Burden the Mitochondrial Quality Control System2018Inngår i: Cells, ISSN 2073-4409, Vol. 7, nr 10, artikkel-id 172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mitochondrial proteome contains proteins from two different genetic systems. Proteins are either synthesized in the cytosol and imported into the different compartments of the organelle or directly produced in the mitochondrial matrix. To ensure proteostasis, proteins are monitored by the mitochondrial quality control system, which will degrade non-native polypeptides. Defective mitochondrial membrane proteins are degraded by membrane-bound AAA-proteases. These proteases are regulated by factors promoting protein turnover or preventing their degradation. Here we determined genetic interactions between the mitoribosome receptors Mrx15 and Mba1 with the quality control system. We show that simultaneous absence of Mrx15 and the regulators of the i-AAA protease Mgr1 and Mgr3 provokes respiratory deficiency. Surprisingly, mutants lacking Mrx15 were more tolerant against proteotoxic stress. Furthermore, yeast cells became hypersensitive against proteotoxic stress upon deletion of MBA1. Contrary to Mrx15, Mba1 cooperates with the regulators of the m-AAA and i-AAA proteases. Taken together, these results suggest that membrane protein insertion and mitochondrial AAA-proteases are functionally coupled, possibly reflecting an early quality control step during mitochondrial protein synthesis.

  • 39. Wanschers, Bas F. J.
    et al.
    Szklarczyk, Radek
    van den Brand, Mariel A. M.
    Jonckheere, An
    Suijskens, Janneke
    Smeets, Roel
    Rodenburg, Richard J.
    Stephan, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Helland, Ingrid B.
    Elkamil, Areej
    Rootwelt, Terje
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    van den Heuvel, Lambert
    Nijtmans, Leo G.
    Huynen, Martijn A.
    A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability2014Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, nr 23, s. 6356-6365Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Complex III (cytochrome bc(1)) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T > A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T > A mutation has a causal role in complex III deficiency.

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