Endogenous H2S resists mitochondria-mediated apoptosis in the adrenal glands via ATP5A1 S-sulfhydration in male mice. (15th October 2018)

• Record Type: Journal Article
• Authors: Wang, Changnan; Du, Jiankui; Du, Shufang; Liu, Yujian; Li, Dongxia; Zhu, Xiaoyan; Ni, Xin
• Is Part Of: Molecular and cellular endocrinology. Volume 474(2018)
• Page Start: 65
• Page End: 73
• Publication Date: 2018-10-15
• Subjects: Adrenal -- Mitochondria -- Apoptosis -- Hydrogen sulfide -- ATP5A1 -- S-sulfhydration; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2018.02.011
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: In a previous study, we showed that endogenous hydrogen sulfide (H2 S) 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 H2 S 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 H2 S donor GYY4137. In the model of Y1 cells, the LPS-induced mitochondria-mediated apoptosis and blunt response to ACTH were rescued by GYY4137. The H2 S-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 H2 S. 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 H2 S 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 H2 S maintains mitochondrial function and steroidogenesis in the adrenal glands. Highlights: Decreased H2 S generation causes mitochondrial-mediated apoptosis in adrenal cortex. H2 S reserves LPS-induced adrenal insufficiency via eliminating mitochondrial-mediated apoptosis. S-sulfhydration of ATP5A1 is critical for H2 S maintenance of steroidogenesis in the adrenal glands.