Succinate mediates inflammation-induced adrenocortical dysfunction

• DOI: 10.7554/elife.83064
• Publication Date: 2023-07-14T14:00:44Z
• Authors: Ivona Mateska; Anke Witt; Eman Hagag; Anupam Sinha; Canelif Yilmaz; Evangelia Thanou; Na Sun; Ourania Kolliniati; Maria Patschin; Heba Abdelmegeed; Holger Henneicke; Waldemar Kanczkowski; Ben Wielockx; Christos Tsatsanis; Andreas Dahl; Axel Karl Walch; Ka Wan Li; Mirko Peitzsch; Triantafyllos Cha...; Vasileia Ismini A...
• Keywords: Proteomics; 0301 basic medicine; QH301-705.5; Science; Succinic Acid; immunology; Mice; 03 medical and health sciences; Adrenocorticotropic Hormone; cell biology; Animals; Biology (General); Glucocorticoids; mouse; Inflammation; adrenal gland; glucocorticoids; DNMT1; Q; R; Cell Biology; succinate dehydrogenase; succinate; 3. Good health; inflammation; IL-1β; Medicine

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.