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MtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming

ABSTRACT: Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion-immunity-metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mtDNA–ZBP1–RIPK3-MLKL axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mitochondrial DNA (mtDNA), which is subsequently taken up by microglia and triggers cGAS-STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor co-agonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS-STING activation and D-serine act as important drivers of epilepsy initiation, offering new mechanistic insights into neuron-microglia-astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.

ORGANISM(S): Mus musculus

PROVIDER: GSE319015 | GEO | 2026/02/11

REPOSITORIES: GEO

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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MtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming

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