MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.

Authors

Feng-Xia Ma, Min Wang, Shuo-Yan Fang, Xiao-Xin Wang, Shen-Han Xu, Xin-Xin Zhao, Yu-Xiao Liu, Cong Wang, Chen Qiao, Qiu-Ling Wang, Lei Cao

Published in

Science advances. Volume 12. Issue 42. Pages eaed8795. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)-associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed Mfn2 up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated MFN2 expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of Mfn2 restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry-based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on Mfn2. Normalization of MFN2 expression through astrocytic Mfn2 knockdown or Stat1 overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2-STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.

PMID:
42886804
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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