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Mateska, I.* ; Witt, A.* ; Hagag, E.* ; Sinha, A.* ; Yilmaz, C.* ; Thanou, E.* ; Sun, N. ; Kolliniati, O.* ; Patschin, M.* ; Abdelmegeed, H.* ; Henneicke, H.* ; Kanczkowski, W.* ; Wielockx, B.* ; Tsatsanis, C.* ; Dahl, A.* ; Walch, A.K. ; Li, K.W.* ; Peitzsch, M.* ; Chavakis, T.* ; Alexaki, V.I.*

Succinate mediates inflammation-induced adrenocortical dysfunction.

eLife 12:34 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dnmt1 ; Il-1β ; Adrenal Gland ; Cell Biology ; Glucocorticoids ; Immunology ; Inflammation ; Mouse ; Succinate ; Succinate Dehydrogenase; Adrenal-gland; Cortisol-levels; Complex-ii; Cell; Dehydrogenase; Star; Steroidogenesis; Insufficiency; Interleukin-1; Mitochondria
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Zeitschrift eLife
Quellenangaben Band: 12, Heft: , Seiten: , Artikelnummer: 34 Supplement: ,
Verlag eLife Sciences Publications
Verlagsort Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Analytical Pathology (AAP)
Förderungen Deutsche Forschungsgemeinschaft