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dc.contributor.authorGrings, Mateuspt_BR
dc.contributor.authorSeminotti, Biancapt_BR
dc.contributor.authorKarunanidhi, Anuradhapt_BR
dc.contributor.authorGonzalez, Lina Ghaloulpt_BR
dc.contributor.authorMohsen, Al-Walidpt_BR
dc.contributor.authorWipf, Peterpt_BR
dc.contributor.authorPalmfeldt, Johanpt_BR
dc.contributor.authorVockley, Jerrypt_BR
dc.contributor.authorLeipnitz, Guilhianpt_BR
dc.date.accessioned2020-02-06T04:17:02Zpt_BR
dc.date.issued2019pt_BR
dc.identifier.issn2045-2322pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/205454pt_BR
dc.description.abstractEthylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) defciencies are hereditary disorders that afect the catabolism of sulfur-containing amino acids. ETHE1 defciency is caused by mutations in the ETHE1 gene, while MoCo defciency is due to mutations in one of three genes involved in MoCo biosynthesis (MOCS1, MOCS2 and GPHN). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical fndings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fbroblasts from four patients with ETHE1 defciency and one with MOCS1 defciency. The efect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identifed in the same cells, while variable alterations in mitochondrial fusion and fssion were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 defciencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofScientific reports. London. Vol. 9, no. 1 (Sep. 2019), 12651, 13 p.pt_BR
dc.rightsOpen Accessen
dc.subjectAminoácidos sulfúricospt_BR
dc.subjectDoenças genéticas inataspt_BR
dc.subjectSulfito oxidasept_BR
dc.titleETHE1 and MOCS1 deficiencies : disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblastspt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb001107868pt_BR
dc.type.originEstrangeiropt_BR


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