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-mitochondrial DNA (mtDNA)–ZBP1–RIPK3–mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (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 coagonist 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 mechanistic insights into neuron–microglia–astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Jie Jiang
Meiling Zuo
College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University
Kehan Zhao
College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University
Zhihao Ling
College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University
Zhida Wu
College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan University
Dongfang Xue
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology
Shouyong Mo
Department of Laboratory Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University
Yuanhui Liu
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology
Yongjun Chen
Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China
Jie Wang
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences Beijing China
Bin Lu
The University of Tokyo , , ,
Chuanzhou Li
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology
Yaqi Duan
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology
He He
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology
Zhiyin Song
Institute of pathology, Tongji Hospital, School of Basic Medicine, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Tongji Medical College, Huazhong University of Science and Technology