INFLAMMATION–INDUCED DOWNREGULATION OF SUCCINATE DEHYDROGENASE REGULATES ADRENOCORTICAL FUNCTION

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of glucocorticoids by the adrenal cortex. In turn, glucocorticoids exert potent anti-inflammatory effects. Severe inflammation may reduce adrenal gland responsiveness to adrenocorticotropic hormone (ACTH) although the underlying molecular mechanisms are poorly understood. Here, we show by transcriptomic, proteomics and metabolomics analysis that lipopolysaccharide (LPS)-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress. We demonstrate that although inflammation disrupts the TCA cycle at the levels of succinate dehydrogenase (SDH) and isocitrate dehydrogenase 2 (IDH2) leading to accumulation of succinate and isocitrate, respectively, only reduced SDH activity and increased succinate levels associate with disturbed steroidogenic capacity of adrenocortical cells. Specifically, IL1β reduces Sdhb expression and steroidogenesis in adrenocortical cells. These findings suggest that SDH activity is important for adrenocortical steroidogenesis and provide a link between inflammation and adrenocortical dysfunction through alterations in the TCA cycle. ### Competing Interest Statement The authors have declared no competing interest.