%0 Journal Article
%A Wischhof, Lena
%A John Mathew, Amal
%A Bonaguro, Lorenzo
%A Beyer, Marc
%A Ehninger, Dan
%A Nicotera, Pierluigi
%A Bano, Daniele
%T Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli
%J Scientific reports
%V 14
%N 1
%@ 2045-2322
%C [London]
%I Macmillan Publishers Limited, part of Springer Nature
%M DZNE-2024-01317
%P 27182
%D 2024
%X Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.
%K Astrocytes: metabolism
%K Astrocytes: drug effects
%K Humans
%K Electron Transport Complex I: metabolism
%K Electron Transport Complex I: genetics
%K Electron Transport Complex I: antagonists & inhibitors
%K Mitochondria: metabolism
%K Oxidative Phosphorylation: drug effects
%K Induced Pluripotent Stem Cells: metabolism
%K Induced Pluripotent Stem Cells: cytology
%K Cell Differentiation
%K Epigenesis, Genetic
%K Neural Stem Cells: metabolism
%K Neural Stem Cells: drug effects
%K Inflammation: metabolism
%K Inflammation: pathology
%K Cells, Cultured
%K Animals
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39516523
%2 pmc:PMC11549212
%R 10.1038/s41598-024-78434-y
%U https://pub.dzne.de/record/272912