Journal Article

DZNE-2024-01317

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli

Wischhof, L. (First author)DZNE* ; John Mathew, A.DZNE* ; Bonaguro, L.DZNE* ; Beyer, M.DZNE* ; Ehninger, D.DZNE* ; Nicotera, P.DZNE* ; Bano, D. (Last author)DZNE*

2024
Macmillan Publishers Limited, part of Springer Nature [London]

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41598-024-78434-y

Abstract: 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.

Keyword(s): Astrocytes: metabolism (MeSH) ; Astrocytes: drug effects (MeSH) ; Humans (MeSH) ; Electron Transport Complex I: metabolism (MeSH) ; Electron Transport Complex I: genetics (MeSH) ; Electron Transport Complex I: antagonists & inhibitors (MeSH) ; Mitochondria: metabolism (MeSH) ; Oxidative Phosphorylation: drug effects (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Cell Differentiation (MeSH) ; Epigenesis, Genetic (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Neural Stem Cells: drug effects (MeSH) ; Inflammation: metabolism (MeSH) ; Inflammation: pathology (MeSH) ; Cells, Cultured (MeSH) ; Animals (MeSH)

---

Contributing Institute(s):

1. Aging and Neurodegeneration (AG Bano)
2. Immunogenomics and Neurodegeneration (AG Beyer)
3. Platform for Single Cell Genomics and Epigenomics (PRECISE)
4. Translational Biogerontology (AG Ehninger)
5. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2024

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---