CBS and CSE are critical for maintenance of mitochondrial function and glucocorticoid production in adrenal cortex.
OBJECTIVE
Mitochondria are known to play a central role in adrenocortical steroidogenesis. Recently, hydrogen sulfide (H2S), a gaseous transmitter endogenously produced by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), has been found to improve mitochondrial function. The present study aimed at examining whether CBS and CSE are expressed in adrenal glands, and investigated the role of these enzymes in the maintenance of mitochondrial function and the production of glucocorticoids in adrenocortical cells.


RESULTS
Both CBS and CSE are present in murine adrenocortical cells and account for H2S generation in adrenal glands. Using a combination of both in vivo and in vitro approaches, we demonstrated that either CBS/CSE inhibitors or small interfering RNAs led to mitochondrial oxidative stress and dysfunction, which meanwhile resulted in blunted corticosterone responses to adrenocorticotropic hormone (ACTH). These effects were significantly attenuated by the treatment of H2S donor GYY4137. Lipopolysaccharide (LPS) also caused mitochondrial damage, thereby resulting in adrenal insufficiency. Moreover, LPS inhibited CBS/CSE expression and H2S production in adrenal glands, while H₂S donor GYY4137 protected against LPS-induced mitochondrial damage and hyporesponsiveness to ACTH. Local suppression of CBS or CSE in adrenal glands significantly increased the mortality in endotoxemic mice, which was also improved by GYY4137.


METHODS
The identification of endogenous H2S generation as critical regulators of adrenocortical responsiveness might result in the development of new therapeutic approaches for the treatment of relative adrenal insufficiency during sepsis.


CONCLUSIONS
Endogenous H₂S plays a critical role in the maintenance of mitochondrial function in the adrenal cortex, thereby resulting in an adequate adrenocortical response to ACTH.
1 The Key Laboratory of Molecular Neurobiology of Ministry of Education, Department of Physiology, Second Military Medical University , Shanghai, China .
Chang-Nan
CN
Wang
Yu-Jian
YJ
Liu
Guo-Li
GL
Duan
Wei
W
Zhao
Xiao-Han
XH
Li
Xiao-Yan
XY
Zhu
Xin
X
Ni
D000302:Adrenal Cortex / Q000187:drug effects / Q000201:enzymology*; D000324:Adrenocorticotropic Hormone; D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D019446:Endotoxemia; D005938:Glucocorticoids / Q000096:biosynthesis*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009025:Morpholines / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D034741:RNA, Small Interfering
C529376:GYY 4137; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D034741:RNA, Small Interfering; D000324:Adrenocorticotropic Hormone; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D003345:Corticosterone; D006862:Hydrogen Sulfide