NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice
Nicotinamide 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 d...
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| Format: | Article |
| Language: | English |
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BioScientifica
2018
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| Subjects: | |
| Online Access: | https://repository.londonmet.ac.uk/1409/1/JOE-16-0638-accepted%20pdf.full.pdf |
| _version_ | 1825624776849227776 |
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| author | Meimaridou, Eirini Goldsworthy, Michelle Chortis, Vasileios Fragouli, Elpida Foster, Paul A. Arlt, Wiebke Cox, Roger D. Metherell, Louise A. |
| author_facet | Meimaridou, Eirini Goldsworthy, Michelle Chortis, Vasileios Fragouli, Elpida Foster, Paul A. Arlt, Wiebke Cox, Roger D. Metherell, Louise A. |
| author_sort | Meimaridou, Eirini |
| collection | LMU |
| description | Nicotinamide 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 inactivatingmutation 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(C57BL/6J). The following results were obtained. Our data suggest thatdeletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (and) and steroidogenic () 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. |
| first_indexed | 2024-07-09T03:46:59Z |
| format | Article |
| id | oai:repository.londonmet.ac.uk:1409 |
| institution | London Metropolitan University |
| language | English |
| last_indexed | 2024-07-09T03:46:59Z |
| publishDate | 2018 |
| publisher | BioScientifica |
| record_format | eprints |
| spelling | oai:repository.londonmet.ac.uk:14092020-06-04T10:10:03Z https://repository.londonmet.ac.uk/1409/ NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice Meimaridou, Eirini Goldsworthy, Michelle Chortis, Vasileios Fragouli, Elpida Foster, Paul A. Arlt, Wiebke Cox, Roger D. Metherell, Louise A. 570 Life sciences; biology Nicotinamide 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 inactivatingmutation 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(C57BL/6J). The following results were obtained. Our data suggest thatdeletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (and) and steroidogenic () 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. BioScientifica 2018-01-12 Article PeerReviewed text en https://repository.londonmet.ac.uk/1409/1/JOE-16-0638-accepted%20pdf.full.pdf Meimaridou, Eirini, Goldsworthy, Michelle, Chortis, Vasileios, Fragouli, Elpida, Foster, Paul A., Arlt, Wiebke, Cox, Roger D. and Metherell, Louise A. (2018) NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice. Journal of Endocrinology, 236 (1). pp. 13-28. ISSN 1479-6805 10.1530/JOE-16-0638 10.1530/JOE-16-0638 |
| spellingShingle | 570 Life sciences; biology Meimaridou, Eirini Goldsworthy, Michelle Chortis, Vasileios Fragouli, Elpida Foster, Paul A. Arlt, Wiebke Cox, Roger D. Metherell, Louise A. NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title | NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title_full | NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title_fullStr | NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title_full_unstemmed | NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title_short | NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| title_sort | nnt is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice |
| topic | 570 Life sciences; biology |
| url | https://repository.londonmet.ac.uk/1409/1/JOE-16-0638-accepted%20pdf.full.pdf |
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