I Function, therefore I am: Overcoming skepticism about mitochondrial supercomplexes

The mitochondrial respiratory chain is believed to dynamically arrange in suprastructures known as supercomplexes or respirasomes, though their function remains elusive. A recent study in Science (Lapuente-Brun et al., 2013) now reports that dynamic supercomplex assembly determines electron flux from different substrates through the respiratory chai

Defects in the biosynthesis of mitochondrial heme c and heme a in yeast and mammals

AbstractDefects in heme biosynthesis have been associated with a large number of diseases, but mostly recognized in porphyrias, which are neurovisceral or cutaneous disorders caused by the accumulation of biosynthetic intermediates. However, defects in the maturation of heme groups that are part of the oxidative phosphorylation system are now also recognized as important causes of disease. The electron transport chain contains heme groups of the types a, b and c, all of which are directly involved in electron transfer reactions. In this article, we review the effect of mutations in enzymes involved in the maturation of heme a (the prosthetic group of cytochrome c oxidase) and heme c (the prosthetic group of cytochrome c) both in yeast and in humans. COX10 and COX15 are two genes, initially identified in Saccharomyces cerevisiae that have been found to cause infantile cytochrome c oxidase deficiency in humans. They participate in the farnesylation and hydroxylation of heme b, steps that are necessary for the formation of heme a, the prosthetic group required for cytochrome oxidase assembly and activity. Deletion of the cytochrome c heme lyase gene in a single allele has also been associated with a human disease, known as Microphthalmia with Linear Skin defects (MLS) syndrome. The cytochrome c heme lyase is necessary to covalently attach the heme group to the apocytochrome c polypeptide. The production of mouse models recapitulating these diseases is providing novel information on the pathogenesis of clinical syndromes

The DEAD Box Protein Mrh4 Functions in the Assembly of the Mitochondrial Large Ribosomal Subunit

SummaryProteins in a cell are universally synthesized by ribosomes. Mitochondria contain their own ribosomes, which specialize in the synthesis of a handful of proteins required for oxidative phosphorylation. The pathway of mitoribosomal biogenesis and factors involved are poorly characterized. An example is the DEAD box proteins, widely known to participate in the biogenesis of bacterial and cytoplasmic eukaryotic ribosomes as either RNA helicases or RNA chaperones, whose mitochondrial counterparts remain completely unknown. Here, we have identified the Saccharomyces cerevisiae mitochondrial DEAD box protein Mrh4 as essential for large mitoribosome subunit biogenesis. Mrh4 interacts with the 21S rRNA, mitoribosome subassemblies, and fully assembled mitoribosomes. In the absence of Mrh4, the 21S rRNA is matured and forms part of a large on-pathway assembly intermediate missing proteins Mrpl16 and Mrpl39. We conclude that Mrh4 plays an essential role during the late stages of mitoribosome assembly by promoting remodeling of the 21S rRNA-protein interactions

Coordination of metal center biogenesis in human cytochrome c oxidase

Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa3- copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbors the CuB site that tightly associates with heme a3 while the COX2 subunit contains the binuclear CuA site. Here, we report that in human cells the CcO copper chaperones form macromolecular assemblies and cooperate with several twin CX9C proteins to control heme a biosynthesis and coordinate copper transfer sequentially to the CuA and CuB sites. These data on CcO illustrate a mechanism that regulates the biogenesis of macromolecular enzymatic assemblies with several catalytic metal redox centers and prevents the accumulation of cytotoxic reactive assembly intermediates

BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome

The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from “multiple mitochondrial dysfunction” syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly

Oma1 Links Mitochondrial Protein Quality Control and TOR Signaling To Modulate Physiological Plasticity and Cellular Stress Responses

ACKNOWLEDGMENTS We thank Dennis Winge (University of Utah) and the members of the Khalimonchuk laboratory for critical comments. We also thank Christoph Schuller (University of Natural Resources, Austria) and Paul Herman (Ohio State University) for reagents. We acknowledge the expert technical assistance of Nataliya Zahayko. We also thank Donna MacCallum for help with the Candida virulence assays. This research was supported by grants from the NIH (P30GM103335 and 5R01GM108975 [O.K.], GM071775-06 and GM105781-01 [A.B.], DK079209 [J.L.]), the U.K. Biotechnology and Biological Research Council (BB/K017365/1 [A.J.P.B.]), the U.K. Medical Research Council (MR/ M026663/1 [A.J.P.B.]), and the European Research Council (C-2009- AdG-249793 [A.J.P.B.]). We declare that we have no competing financial interests. FUNDING INFORMATION This work, including the efforts of Alistair J. P. Brown, was funded by Biotechnology and Biological Research Counsil (BB/K017365/1). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (5R01GM108975). This work, including the efforts of Oleh Khalimonchuk, was funded by HHS | National Institutes of Health (NIH) (P30GM103335).This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM071775-06). This work, including the efforts of Antoni Barrientos, was funded by HHS | National Institutes of Health (NIH) (GM105781-01). This work, including the efforts of Jaekwon Lee, was funded by HHS | National Institutes of Health (NIH) (DK079209). This work, including the efforts of Alistair J. P. Brown, was funded by Medical Research Council (MRC) (MR/M026663/1). This work, including the efforts of Alistair J. P. Brown, was funded by EC | European Research Council (ERC) (C-2009-AdG-249793).Peer reviewedPublisher PD

Estudio hidrogeológico para el diseño de métodos de recarga de acuíferos en la microcuenca de Unuhuaycco, distrito Oropesa, provincia Quispicanchi - Cusco -2019

El área de estudio se encuentra en el departamento de Cusco, Provincia Quispicanchi, Distrito Oropesa en la microcuenca Unuhuaycco, siendo esta accesible por la pista principal Cusco – Sicuani, sobre esta vía a la altura del distrito de oropesa, se sigue por una vía asfaltada hasta el mismo centro poblado; a partir de allí existe una trocha carrozable que atraviesa por el poblado de Patacalle hasta llegar a la comunidad de Pucara que se ubica en cabecera de cuenca. A nivel regional, morfoestructuralmente la zona de estudio se encuentra en la zona intermedia Altiplano – Cordillera Oriental, donde se identificó las unidades fisiográficas en la microcuenca Unuhuaycco a partir de la identificación de unidades de gran paisaje, unidades de paisaje, y unidades de subpaisaje, partiendo del mapa de pendientes. Posteriormente se integraron estas unidades fisiográficas con la litología, obteniéndose así las unidades geomorfológicas locales correspondientes para la zona de estudio. En el aspecto geológico la microcuenca Unuhuaycco se caracteriza por presentar las Formaciones: Pachatusán, Huambutio, Huancané, Paucarbamba, Quilque, Rumicolca y depósitos cuaternarios (aluviales, glaciares, coluviales y fluviales). El área de estudio presenta fallas normales Pachatuáan y Tambomachay que se encuentra en la parte baja de la microcuenca. En el aspecto hidrológico al realizar el análisis y regionalización de las condiciones meteorológicas de la microcuenca Unuhuaycco se tomó como altitud media de 3657 m.s.n.m obteniendo para el mismo una precipitación anual de 669.97 mm/año y una temperatura media mensual de 9.9 °C. Con respecto a la hidrogeología en la microcuenca Unuhuaycco se han inventariado 16 fuentes de agua, 4 puntos de control y también se han identificado dos unidades hidrogeológicas divididas de la siguiente forma: acuíferos que ocupan un área total de 294.18 hectáreas dentro del cual se encuentran acuíferos porosos non consolidados, fisurados sedimentarios y volcánico sedimentarios y acuitardos ocupando un área total de 534.15 ha dentro de la cual se encuentran acuitardos no consolidados, sedimentarios y volcánicos. Con respecto al balance hídrico la oferta hídrica o cantidad de agua con la que cuenta la microcuenca Unuhuaycco es de 918,203.74 m3/año y con respecto a la demanda de agua esta se ha dividido en tres: una demanda hídrica por consumo humano de 450903.45 m3/año, por consumo pecuario 3650.00 m3/año y demanda para riego de 1020820.41 m3/año, con una demanda total de 1475373.87 m3/año. En los diseños de métodos de recarga de acuíferos se plantearon las zanjas de infiltración, zanjas de infiltración con una forestación intermedia siendo esta una práctica de fácil realización que intercepta el agua de escorrentía facilitando su infiltración al suelo las cuales en laderas muy degradas con pendientes que van entre 50 y 75% permite la recuperación de la vegetación en dichas laderas. El presente estudio servirá de herramienta de consulta para iniciar futuras investigaciones en el manejo y buena gestión del recurso hídrico y un aporte en la toma de decisiones de las autoridades del poblado de Oropesa.Tesi

Mitochondrial complex I plays an essential role in human respirasome assembly

The assembly and function of the mitochondrial respiratory chain (RC) involve the organization of RC enzyme complexes in supercomplexes or respirasomes through an unknown biosynthetic process. This leads to structural interdependences between RC complexes, which are highly relevant from biological and biomedical perspectives, because RC defects lead to severe human disorders. We show that in human cells, respirasome biogenesis involves a complex I assembly intermediate acting as a scaffold for the combined incorporation of complexes III and IV subunits, rather than originating from the association of preassembled individual holoenzymes. The process ends with the incorporation of complex I NADH dehydrogenase catalytic module, which leads to the respirasome activation. While complexes III and IV assemble either as free holoenzymes or by incorporation of free subunits into supercomplexes, the respirasomes constitute the structural units where complex I is assembled and activated, thus explaining the functional significance of the respirasomes for RC function

El género Anyphaena Sundevall, 1833 (Araneae: Anyphaenidae) en la Península Ibérica

En este trabajo se caracterizan adecuadamente las cuatro especies del género Anyphaena Sundevall, 1833, actualmente conocidas de la Península Ibérica, se recopilan las citas dadas hasta la fecha y se aportan nuevas localidades, así como algunos datos sobre su fenología, distribución y hábitat específico. Se propone y discute el establecimiento de una nueva sinonimia (A. occidentalis Simon, sinónimo de A. numida Simon) y se ofrece una clave dicotómica para la identificación de los adultos.The four especies of the genus Anyphaena Sundevall, 1833, actualy known on the Iberian Peninsula, are characterized. We give the previous and new localities, some data concerning your distribution, phenology, and especific habitat. A new synonimy (A. occidentalis Simon, synonimous of A. numida Simon) is prposed and discussed. A dichotomous key for the male and female identification is given

hCOA3 stabilizes COX1 and promotes cytochrome c oxidase assembly in human mitochondria

Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency