Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice

BACKGROUND: Depression is a common psychiatric disorder characterized by heightened stress exposure and disruptions in neuronal signaling. Growing evidence suggests that mitochondrial dysfunction contributes to its pathophysiology. In particular, mitochondrial dynamics regulated by Dnm1l/Drp1 are critical for neuronal homeostasis, and their dysregulation may lead to cellular impairment. Additionally, mitochondrial-endoplasmic reticulum contact sites (MERCs) are crucial for maintaining cellular function and require precise regulation. However, the role of Drp1 in modulating MERC structure and function in the context of depression remains unclear. METHODS: We quantified protein changes via 4D-FastDIA proteomics. MERC alterations were examined using transmission electron microscopy (TEM) and proximity ligation assay (PLA). Mitochondrial metabolism was assessed with the Seahorse XF Analyzer. Autophagy was visualized through tyramine signal amplification and Imaris-based 3D reconstruction. The causal relationship was tested using Vglut2-Cre mice combined with specific flox-virus mediated Drp1 manipulation and pharmacological inhibition of autophagy. Depression-like behaviors were evaluated after chronic social defeat stress (CSDS). RESULTS: Drp1 activation disrupts mitochondrial-endoplasmic reticulum contact sites (MERCs), leading to mitochondrial dysfunction and impaired autophagy, and ultimately promoting depressive-like behaviors. Inhibiting the MERC tethering protein GRP75 or enhancing mitophagy pharmacologically alleviated these neuronal and behavioral deficits. These findings identify Drp1-mediated MERC disruption as a key mechanism in depression and suggest therapeutic strategies targeting MERC integrity and autophagy. CONCLUSION: Our results provide novel mechanistic evidence that Drp1-mediated dysfunction at MERCs and impaired mitochondrial quality control contribute to the pathogenesis of depression. These findings underscore the importance of endoplasmic reticulum-mitochondrial crosstalk in depression and suggest potential therapeutic targets for modulating cellular resilience in stress-related disorders.