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000272912 1001_ $$0P:(DE-2719)2811527$$aWischhof, Lena$$b0$$eFirst author$$udzne
000272912 245__ $$aMitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli
000272912 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2024
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000272912 520__ $$aInhibition 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.
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000272912 650_2 $$2MeSH$$aAstrocytes: metabolism
000272912 650_2 $$2MeSH$$aAstrocytes: drug effects
000272912 650_2 $$2MeSH$$aHumans
000272912 650_2 $$2MeSH$$aElectron Transport Complex I: metabolism
000272912 650_2 $$2MeSH$$aElectron Transport Complex I: genetics
000272912 650_2 $$2MeSH$$aElectron Transport Complex I: antagonists & inhibitors
000272912 650_2 $$2MeSH$$aMitochondria: metabolism
000272912 650_2 $$2MeSH$$aOxidative Phosphorylation: drug effects
000272912 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000272912 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: cytology
000272912 650_2 $$2MeSH$$aCell Differentiation
000272912 650_2 $$2MeSH$$aEpigenesis, Genetic
000272912 650_2 $$2MeSH$$aNeural Stem Cells: metabolism
000272912 650_2 $$2MeSH$$aNeural Stem Cells: drug effects
000272912 650_2 $$2MeSH$$aInflammation: metabolism
000272912 650_2 $$2MeSH$$aInflammation: pathology
000272912 650_2 $$2MeSH$$aCells, Cultured
000272912 650_2 $$2MeSH$$aAnimals
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000272912 7001_ $$0P:(DE-2719)9002538$$aJohn Mathew, Amal$$b1$$udzne
000272912 7001_ $$0P:(DE-2719)9001512$$aBonaguro, Lorenzo$$b2$$udzne
000272912 7001_ $$0P:(DE-2719)2812219$$aBeyer, Marc$$b3$$udzne
000272912 7001_ $$0P:(DE-2719)2289209$$aEhninger, Dan$$b4$$udzne
000272912 7001_ $$0P:(DE-2719)2010732$$aNicotera, Pierluigi$$b5$$udzne
000272912 7001_ $$0P:(DE-2719)2158358$$aBano, Daniele$$b6$$eLast author$$udzne
000272912 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-024-78434-y$$gVol. 14, no. 1, p. 27182$$n1$$p27182$$tScientific reports$$v14$$x2045-2322$$y2024
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