المؤلفون: Staiano, C, García-Corzo, L, Mantle, D, Turton, N, Millichap, LE, Brea-Calvo, G, Hargreaves, I

مصطلحات موضوعية: RS Pharmacy and materia medica

الوصف: Originally identified as a key component of the mitochondrial respiratory chain, Co enzyme Q (CoQ or CoQ10 for human tissues) has recently been revealed to be essential for many different redox processes, not only in the mitochondria, but elsewhere within other cellular membrane types. Cells rely on endogenous CoQ biosynthesis, and defects in this still-not completely understood pathway result in primary CoQ deficiencies, a group of conditions biochemically characterised by decreased tissue CoQ levels, which in turn are linked to functional defects. Secondary CoQ deficiencies may result from a wide variety of cellular dysfunctions not directly linked to primary synthesis. In this article, we review the current knowledge on CoQ biosynthesis, the defects leading to diminished CoQ10 levels in human tissues and their associated clinical manifestations.

وصف الملف: text

العلاقة: https://researchonline.ljmu.ac.uk/id/eprint/20484/1/antioxidants-12-01469.pdfTest; Staiano, C, García-Corzo, L, Mantle, D, Turton, N, Millichap, LE, Brea-Calvo, G and Hargreaves, I (2023) Biosynthesis, Deficiency, and Supplementation of Coenzyme Q. Antioxidants, 12 (7). ISSN 2076-3921

الإتاحة: https://doi.org/10.3390/antiox12071469Test
http://researchonline.ljmu.ac.uk/id/eprint/20484Test/
https://researchonline.ljmu.ac.uk/id/eprint/20484/1/antioxidants-12-01469.pdfTest

المؤلفون: Luna-Sanchez M., Beninca C., Cerutti R., Brea-Calvo G., Yeates A., Scorrano L., Zeviani M., Viscomi C.

المساهمون: Luna-Sanchez, M., Beninca, C., Cerutti, R., Brea-Calvo, G., Yeates, A., Scorrano, L., Zeviani, M., Viscomi, C.

مصطلحات موضوعية: apoptosi, focal segmental glomerulosclerosi, mitochondrial cristae, mitochondrial DNA depletion, Mpv17, Opa1, oxidative phosphorylation

الوصف: Moderate overexpression of Opa1, the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of this approach in the Mpv17−/− mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1tg mice, we found a surprising anticipation of the severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17−/− animals as a late-onset clinical feature (after 12–18 months of life). In contrast, Mpv17−/− animals from this new “mixed” strain died at 8–9 weeks after birth because of severe kidney failure However, Mpv17−/−::Opa1tg mice lived much longer than Mpv17−/− littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17−/−::Opa1tg than in Mpv17−/− kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17−/−::Opa1tg versus Mpv17−/− kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be effective against mtDNA depletion syndromes. No treatment is currently available to syndromes associated to mitochondrial DNA instability. We investigated the possibility to correct the kidney disease typical of Mpv17−/− mice by transgenically overexpressing Opa1, the master regulator of mitochondrial cristae shape. Mpv17−/−::Opa1 double recombinant mice showed a marked prolongation of the lifespan, with correction of the proteinuria and of the focal segmental glomerulosclerosis, by reducing apoptosis in podocytes. Accordingly, ...

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32562616; info:eu-repo/semantics/altIdentifier/wos/WOS:000560007200020; journal:MOLECULAR THERAPY; http://hdl.handle.net/11577/3344055Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85086786617

الإتاحة: https://doi.org/10.1016/j.ymthe.2020.06.010Test
http://hdl.handle.net/11577/3344055Test

المؤلفون: Dogan S. A., Cerutti R., Beninca C., Brea-Calvo G., Jacobs H. T., Zeviani M., Szibor M., Viscomi C.

المساهمون: Dogan, S. A., Cerutti, R., Beninca, C., Brea-Calvo, G., Jacobs, H. T., Zeviani, M., Szibor, M., Viscomi, C.

مصطلحات موضوعية: alternative oxidase, antioxidant, autophagy, mitochondrial biogenesi, mitochondrial disease, redox signaling, ROS, satellite cell, stress response, Animal, Female, Male, Mice, Inbred C57BL, Knockout, Mitochondrial Myopathie, Mitochondrial Protein, Muscle, Skeletal, Organelle Biogenesi, Oxidation-Reduction, Oxidoreductase, Plant Protein, Reactive Oxygen Specie, Signal Transduction

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/30122554; info:eu-repo/semantics/altIdentifier/wos/WOS:000449440000011; volume:28; issue:5; firstpage:764; lastpage:775.e5; journal:CELL METABOLISM; http://hdl.handle.net/11577/3321416Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85054720281; http://www.cellmetabolism.orgTest/

الإتاحة: https://doi.org/10.1016/j.cmet.2018.07.012Test
http://hdl.handle.net/11577/3321416Test
http://www.cellmetabolism.orgTest/

المؤلفون: Dogan, SA, Cerrutti, R, Benincá, C, Brea-Calvo, G, Jacobs, H T, Zeviani, M, Szibor, M, Viscomi, C

المساهمون: Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, University of Tampere

مصطلحات موضوعية: Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology

وصف الملف: fulltext; 764-775e

العلاقة: Cell Metabolism; 28; https://trepo.tuni.fi/handle/10024/104777Test; URN:NBN:fi:uta-201812133011

الإتاحة: https://trepo.tuni.fi/handle/10024/104777Test

المؤلفون: Alcazar-Fabra M., Rodriguez-Sanchez F., Trevisson E., Brea-Calvo G.

المساهمون: Alcazar-Fabra, M., Rodriguez-Sanchez, F., Trevisson, E., Brea-Calvo, G.

مصطلحات موضوعية: Coenzyme Q primary deficiency, Genotype-phenotype correlation, Mitochondrial disease, Rare disease, Web-based live platform

الوصف: Primary Coenzyme Q (CoQ) deficiencies are clinically heterogeneous conditions and lack clear genotype-phenotype correlations, complicating diagnosis and prognostic assessment. Here we present a compilation of all the symptoms and patients with primary CoQ deficiency described in the literature so far and analyse the most common clinical manifestations associated with pathogenic variants identified in the different COQ genes. In addition, we identified new associations between the age of onset of symptoms and different pathogenic variants, which could help to a better diagnosis and guided treatment. To make these results useable for clinicians, we created an online platform (https://coenzymeQbiology.github.io/clinic-CoQ-deficiencyTest) about clinical manifestations of primary CoQ deficiency that will be periodically updated to incorporate new information published in the literature. Since CoQ primary deficiency is a rare disease, the available data are still limited, but as new patients are added over time, this tool could become a key resource for a more efficient diagnosis of this pathology.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/33677064; info:eu-repo/semantics/altIdentifier/wos/WOS:000646298700001; volume:167; firstpage:141; lastpage:180; numberofpages:40; journal:FREE RADICAL BIOLOGY & MEDICINE; http://hdl.handle.net/11577/3389351Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85102795515

الإتاحة: https://doi.org/10.1016/j.freeradbiomed.2021.02.046Test
http://hdl.handle.net/11577/3389351Test

المؤلفون: Brea-Calvo, G., Haack, T.B., Karall, D., Ohtake, A., Invernizzi, F., Carrozzo, R., Kremer, L.S., Dusi, S., Fauth, C., Scholl-Bürgi, S., Graf, E., Ahting, U., Resta, N., Laforgia, N., Verrigni, D., Okazaki, Y., Kohda, M., Martinelli, D., Freisinger, P., Strom, T.M., Meitinger, T., Lamperti, C., Lacson, A., Navas, P., Mayr, J.A., Bertini, E., Murayama, K., Zeviani, M., Prokisch, H., Ghezzi, D.

المصدر: Am. J. Hum. Genet. 96, 309-317 (2015)

الوصف: Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations inCOQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

وصف الملف: application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/25658047; info:eu-repo/semantics/altIdentifier/wos/WOS:000349276700013; info:eu-repo/semantics/altIdentifier/isbn/0002-9297; info:eu-repo/semantics; https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=43236Test; urn:isbn:0002-9297; urn:issn:0002-9297; urn:issn:1537-6605

الإتاحة: https://doi.org/10.1016/j.ajhg.2014.12.023Test
https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=43236Test

المؤلفون: Dalla Rosa, I, Durigon, R, Pearce, SF, Rorbach, J, Hirst, EMA, Vidoni, S, Reyes, A, Brea-Calvo, G, Minczuk, M, Woellhaf, MW, Herrmann, JM, Huynen, MA, Holt, IJ, Spinazzola, A

المصدر: Nucleic Acids Research , 42 (13) pp. 8500-8515. (2014)

مصطلحات موضوعية: Mitochondria, dna, dna mitochondrial, gene silencing, mitochondrial proteins, ribosomes, sucrose, nucleoid, mitochondrial ribosomes

الوصف: MPV17 is a mitochondrial protein of unknown function, and mutations in MPV17 are associated with mitochondrial deoxyribonucleic acid (DNA) maintenance disorders. Here we investigated its most similar relative, MPV17L2, which is also annotated as a mitochondrial protein. Mitochondrial fractionation analyses demonstrate MPV17L2 is an integral inner membrane protein, like MPV17. However, unlike MPV17, MPV17L2 is dependent on mitochondrial DNA, as it is absent from ρ0 cells, and co-sediments on sucrose gradients with the large subunit of the mitochondrial ribosome and the monosome. Gene silencing of MPV17L2 results in marked decreases in the monosome and both subunits of the mitochondrial ribosome, leading to impaired protein synthesis in the mitochondria. Depletion of MPV17L2 also induces mitochondrial DNA aggregation. The DNA and ribosome phenotypes are linked, as in the absence of MPV17L2 proteins of the small subunit of the mitochondrial ribosome are trapped in the enlarged nucleoids, in contrast to a component of the large subunit. These findings suggest MPV17L2 contributes to the biogenesis of the mitochondrial ribosome, uniting the two subunits to create the translationally competent monosome, and provide evidence that assembly of the small subunit of the mitochondrial ribosome occurs at the nucleoid.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/1546410/1/Spinazzola_gku513.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1546410Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/1546410/1/Spinazzola_gku513.pdfTest
https://discovery.ucl.ac.uk/id/eprint/1546410Test/

المؤلفون: Johnson, MA, Vidoni, S, Durigon, R, Pearce, SF, Rorbach, J, He, J, Brea-Calvo, G, Minczuk, M, Reyes, A, Holt, IJ, Spinazzola, A

المساهمون: Lightowlers, R

المصدر: PLOS ONE , 9 (4) , Article e93597. (2014)

الوصف: Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation.

وصف الملف: text

العلاقة: https://discovery.ucl.ac.uk/id/eprint/1546412/1/Spinazzola_journal.pone.0093597.PDFTest; https://discovery.ucl.ac.uk/id/eprint/1546412Test/

الإتاحة: https://discovery.ucl.ac.uk/id/eprint/1546412/1/Spinazzola_journal.pone.0093597.PDFTest
https://discovery.ucl.ac.uk/id/eprint/1546412Test/

المؤلفون: Acosta Lopez M. J., Trevisson E., Canton M., Vazquez-Fonseca L., Morbidoni V., Baschiera E., Frasson C., Pelosi L., Rascalou B., Desbats M. A., Alcazar-Fabra M., Rios J. J., Sanchez-Garcia A., Basso G., Navas P., Pierrel F., Brea-Calvo G., Salviati L.

المساهمون: Acosta Lopez, M. J., Trevisson, E., Canton, M., Vazquez-Fonseca, L., Morbidoni, V., Baschiera, E., Frasson, C., Pelosi, L., Rascalou, B., Desbats, M. A., Alcazar-Fabra, M., Rios, J. J., Sanchez-Garcia, A., Basso, G., Navas, P., Pierrel, F., Brea-Calvo, G., Salviati, L.

الوصف: Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ10 supplementation. Treatment is however problematic because of the low bioavailability of CoQ10 and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of COQ6, a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional COQ6 using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that COQ6 isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to COQ6 mutations.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/31379988; info:eu-repo/semantics/altIdentifier/wos/WOS:000476787800001; volume:2019; firstpage:1; lastpage:11; numberofpages:11; journal:OXIDATIVE MEDICINE AND CELLULAR LONGEVITY; http://hdl.handle.net/11577/3308556Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85071186544

الإتاحة: https://doi.org/10.1155/2019/3904905Test
http://hdl.handle.net/11577/3308556Test

المؤلفون: Rodríguez-Hernández, Á., Brea-Calvo, G., Fernández-Ayala, D. J. M., Cordero, M., Navas, P., Sánchez-Alcázar, J. A.

المصدر: Apoptosis ; volume 11, issue 3, page 453-453 ; ISSN 1360-8185 1573-675X

مصطلحات موضوعية: Cancer Research, Biochemistry (medical), Cell Biology, Clinical Biochemistry, Pharmaceutical Science, Pharmacology

الإتاحة: https://doi.org/10.1007/s10495-006-7754-7Test