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dc.contributor.authorMeimaridou, Een_US
dc.contributor.authorGoldsworthy, Men_US
dc.contributor.authorChortis, Ven_US
dc.contributor.authorFragouli, Een_US
dc.contributor.authorFoster, PAen_US
dc.contributor.authorArlt, Wen_US
dc.contributor.authorCox, Ren_US
dc.contributor.authorMetherell, LAen_US
dc.description.abstractNicotinamide nucleotide transhydrogenase, NNT, is a ubiquitous protein of the inner mitochondrial membrane with a key role in mitochondrial redox balance. NNT produces high concentrations of NADPH for detoxification of reactive oxygen species by glutathione and thioredoxin pathways. In humans, NNT dysfunction leads to an adrenal-specific disorder, glucocorticoid deficiency. Certain substrains of C57BL/6 mice contain a spontaneously occurring inactivating Nnt mutation and display glucocorticoid deficiency along with glucose intolerance and reduced insulin secretion. To understand the underlying mechanism(s) behind the glucocorticoid deficiency, we performed comprehensive RNA-seq on adrenals from wild-type (C57BL/6N), mutant (C57BL/6J) and BAC transgenic mice overexpressing Nnt (C57BL/6JBAC). The following results were obtained. Our data suggest that Nnt deletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (Prdx3 and Txnrd2) and steroidogenic (Cyp11a1) enzymes. Pathway analysis also revealed upregulation of heat shock protein machinery and haemoglobins possibly in response to the oxidative stress initiated by NNT ablation. In conclusion, using transcriptomic profiling in adrenals from three mouse models, we showed that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression. Further, we demonstrated that both under expression or overexpression of NNT reduced corticosterone output implying a central role for it in the control of steroidogenesis. This is likely due to a reduction in the expression of a key steroidogenic enzyme, Cyp11a1, which mirrored the reduction in corticosterone output.en_US
dc.format.extent13 - 28en_US
dc.relation.ispartofJ Endocrinolen_US
dc.rightsThis work is licensed under a Creative Commons Attribution 3.0 Unported License.
dc.subjectRNA sequencingen_US
dc.subjectROS scavengersen_US
dc.subjectnicotinamide nucleotide transhydrogenaseen_US
dc.subjectredox homeostasisen_US
dc.subjectAdrenal Cortexen_US
dc.subjectCholesterol Side-Chain Cleavage Enzymeen_US
dc.subjectGene Expression Profilingen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectMice, Transgenicen_US
dc.subjectMitochondrial Proteinsen_US
dc.subjectNADP Transhydrogenase, AB-Specificen_US
dc.subjectNADP Transhydrogenasesen_US
dc.subjectOxidative Stressen_US
dc.subjectPeroxiredoxin IIIen_US
dc.subjectSequence Analysis, RNAen_US
dc.subjectThioredoxin Reductase 2en_US
dc.titleNNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice.en_US
dc.rights.holder© 2018 The authors
pubs.notes6 monthsen_US
qmul.funderAntioxidant defence in adrenocortical cells::MRCen_US

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