TY  - JOUR
AU  - Wischhof, Lena
AU  - John Mathew, Amal
AU  - Bonaguro, Lorenzo
AU  - Beyer, Marc
AU  - Ehninger, Dan
AU  - Nicotera, Pierluigi
AU  - Bano, Daniele
TI  - Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli
JO  - Scientific reports
VL  - 14
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2024-01317
SP  - 27182
PY  - 2024
AB  - 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.
KW  - Astrocytes: metabolism
KW  - Astrocytes: drug effects
KW  - Humans
KW  - Electron Transport Complex I: metabolism
KW  - Electron Transport Complex I: genetics
KW  - Electron Transport Complex I: antagonists & inhibitors
KW  - Mitochondria: metabolism
KW  - Oxidative Phosphorylation: drug effects
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: cytology
KW  - Cell Differentiation
KW  - Epigenesis, Genetic
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: drug effects
KW  - Inflammation: metabolism
KW  - Inflammation: pathology
KW  - Cells, Cultured
KW  - Animals
LB  - PUB:(DE-HGF)16
C6  - pmid:39516523
C2  - pmc:PMC11549212
DO  - DOI:10.1038/s41598-024-78434-y
UR  - https://pub.dzne.de/record/272912
ER  -