Mitochondrial Complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli
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ABSTRACT:
PROVIDER: PRJNA1125009 | ENA |
REPOSITORIES: ENA
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Project description: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 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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Project description: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.
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Project description:The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer’s disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
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