Back to Search
Start Over
Endogenous H2S resists mitochondria-mediated apoptosis in the adrenal glands via ATP5A1 S-sulfhydration in male mice
- Source :
- Molecular and Cellular Endocrinology. 474:65-73
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- In a previous study, we showed that endogenous hydrogen sulfide (H2S) plays a key role in the maintenance of intact adrenal cortex function via the protection of mitochondrial function during endoxemia. We further investigated whether mitochondria-mediated apoptosis is involved in H2S protection of adrenal function. LPS treatment resulted in mitochondria-mediated apoptosis in the adrenal glands of male mice, and these effects were prevented by the H2S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137. The H2S-generating enzyme cystathionine-β-synthase (CBS) knockout heterozygous (CBS+/-) mice showed mitochondria-mediated apoptosis in the adrenal gland and adrenal insufficiency. GYY4137 treatment restored adrenal function and eliminated mitochondria-mediated apoptosis. Maleimide assay combined with mass spectrometry analysis showed that a number of proteins in mitochondria were S-sulfhydrated in the adrenal gland. ATP5A1 was further confirmed as S-sulfhydrated using a modified biotin switch assay. The level of S-sulfhydrated ATP5A1 was decreased in the adrenal gland of endotoxemic and CBS+/- mice, which was restored by GYY4137. ATP5A1 was identified as sulfhydrated at cysteine 244 by H2S. Overexpression of the cysteine 244 mutant ATP5A1 in Y1 cells resulted in a loss of LPS-induced mitochondria-mediated apoptosis and GYY4137 restoration of LPS-induced hyporesponsiveness to ACTH. Collectively, the present study revealed that decreased H2S generation leads to mitochondrial-mediated apoptosis in the adrenal cortex and a blunt response to ACTH. S-sulfhydration of ATP5A1 at cysteine 244 is an important molecular mechanism by which H2S maintains mitochondrial function and steroidogenesis in the adrenal glands.
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
medicine.medical_specialty
Adrenal gland
Adrenal cortex
Endogeny
Mitochondrion
equipment and supplies
medicine.disease
Biochemistry
03 medical and health sciences
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Enzyme
chemistry
Apoptosis
Internal medicine
medicine
Adrenal insufficiency
Molecular Biology
Cysteine
Subjects
Details
- ISSN :
- 03037207
- Volume :
- 474
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Endocrinology
- Accession number :
- edsair.doi...........2a9194452d3aa5dfd6845b5c83554dc3