Succinate mediates inflammation-induced adrenocortical dysfunction

• Published in: eLife Vol. 12
• Main Authors: Mateska, Ivona, Witt, Anke, Hagag, Eman, Sinha, Anupam, Yilmaz, Canelif, Thanou, Evangelia, Sun, Na, Kolliniati, Ourania, Patschin, Maria, Abdelmegeed, Heba, Henneicke, Holger, Kanczkowski, Waldemar, Wielockx, Ben, Tsatsanis, Christos, Dahl, Andreas, Walch, Axel Karl, Li, Ka Wan, Peitzsch, Mirko, Chavakis, Triantafyllos, Alexaki, Vasileia Ismini
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 14-07-2023; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: ACTH; Adrenal cortex; adrenal gland; Adrenal glands; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - metabolism; Analysis; Animals; Biosynthesis; Carbohydrates; Cell Biology; Corticosteroids; Dehydrogenases; DNA methylation; DNA methyltransferase; DNMT1; DNMT1 protein; Enzymes; Fatty acids; Genes; glucocorticoids; Glucocorticoids - metabolism; Heparan sulfate; Hypothalamic-pituitary-adrenal axis; Hypothalamus; IL-1β; Immunology and Inflammation; Inflammation; Inflammation - metabolism; Metabolism; Metabolomics; Methylation; Methyltransferases; Mice; Oxidative phosphorylation; Phosphorylation; Pituitary; Proteins; Proteomics; Statistical analysis; Steroidogenesis; succinate; Succinate dehydrogenase; Succinic Acid; Transcriptomics; Tricarboxylic acid cycle; Canada; Germany; succinate; mouse; DNMT1; cell biology; inflammation; adrenal gland; glucocorticoids; IL-1β; immunology; succinate dehydrogenase
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83064

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
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.