Succinate mediates inflammation-induced adrenocortical dysfunction

Abstract

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.

Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland

“…However, our study suggests that the phospholipidomic landscape and the ARA content of mitochondria specifically determines steroidogenesis. On the basis of our findings, we hypothesize that the PUFA content of phospholipids assembling the mitochondrial membrane is critical for proper mitochondrial membrane potential and bioenergetics, which is pivotal for cholesterol transport into mitochondria and steroidogenesis (10,(16)(17)(18)(19).…”

“…1, E to G). Electron transport chain-dependent mitochondrial bioenergetics are intimately linked with and required for steroidogenesis (10,(16)(17)(18)(19). Hence, the observed reduction of the mitochondrial membrane potential (Fig.…”

“…Immunofluerescent stainings were performed as previously described (82). Adrenal glands cleaned from surrounding fat tissue were fixed in 4% PFA in PBS, washed overnight in PBS, cryopreserved in 30% sucrose (AppliChem GmbH) in PBS overnight at 4°C, embedded in Optimal Cutting Temperature (O.C.T.)…”