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Dihuang Yinzi ameliorates post-stroke depression through Miro1 ubiquitination-dependent mitophagy
Hui Chang1, Zhiping Ji2, Qingya Sun2
1Department of rehabilitation, Lianyungang Affiliated Hospital of Nanjing University of Chinese Medicine, No.160, Chaoyang Middle Road, Haizhou District, Lianyungang, 222004, China.
Ethnopharmacological Relevance:
Dihuang Yinzi (DY) is a classic formula traditionally used for stroke-related disorders. Its potential therapeutic effect on post-stroke depression (PSD), however, remains to be investigated.
Aim Of The Study:
This study aims to evaluate the antidepressant effects of DY in a rat model of PSD and to explore the underlying mechanisms involving mitophagy and neuroinflammation.
Materials And Methods:
PSD was induced in rats by middle cerebral artery occlusion combined with chronic unpredictable mild stress. DY extract was administered daily for two weeks. Neurofunctional deficits and depressive-like behaviors were assessed. Cerebral infarction volume was measured by TTC staining. Hippocampal tissues were collected for transcriptomic analysis, qPCR, Western blot, immunoprecipitation, and ELISA to detect mitophagy-related genes (RHOT1, MAP1LC3B, PINK1, PRKN) and proteins as well as inflammatory factors. A specific mitophagy inhibitor was used to verify whether the anti-inflammatory effects of DY depend on mitophagy. Subcellular fractionation and immunofluorescence co-localization with the mitochondrial marker Tom20 were performed to confirm mitochondrial localization of overexpressed Miro1. The role of Miro1 was further validated using adenovirus-mediated overexpression.
Results:
DY significantly alleviated depressive-like behaviors and reduced cerebral infarction volume in PSD rats. qPCR analysis showed that DY downregulated RHOT1 (Miro1) and upregulated MAP1LC3B, PINK1, and PRKN mRNA expression. Transcriptomic and mechanistic analyses revealed that DY promoted Miro1 degradation, thereby enhancing PINK1-mediated mitophagy. Subcellular fractionation and immunofluorescence confirmed that overexpressed Miro1 was correctly localized to mitochondria. Inhibition of mitophagy abolished the anti-inflammatory effects of DY, as evidenced by increased NF-κB activation and elevated pro-inflammatory cytokine levels. Notably, adenovirus-mediated Miro1 overexpression reversed the therapeutic effects of DY.
Conclusions:
DY improves PSD by promoting Miro1 degradation to facilitate mitophagy and suppress NF-κB-mediated neuroinflammation. These findings provide a scientific basis for the clinical application of DY in PSD and identify Miro1 as a potential therapeutic target.
