Running exercise alleviates depressive-like behaviors through the activation of PINK1-Parkin mediated mitophagy in mice exposed to chronic social defeat stress

Sep 5, 2025Psychiatry research

Running exercise may reduce depression-like behaviors by activating cell cleanup processes in stressed mice

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Abstract

Running exercise significantly ameliorated depressive-like behaviors in mice subjected to chronic social defeat stress.

Chronic social defeat stress induced depressive-like behaviors and impaired hippocampal function in male BALB/c mice.
Running exercise improved both behavioral symptoms and neuronal function in these mice.
Activation of a specific mitophagy pathway (PINK1-Parkin) was linked to the benefits of running exercise.
SIRT1 expression in the hippocampus was found to be upregulated by running exercise, countering its downregulation due to stress.
Inhibiting SIRT1 negated the antidepressant effects of running and led to the emergence of depressive-like behaviors.

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AIMS: Running exercise has demonstrated efficacy in the prevention and treatment of depression, yet the underlying mechanisms remain incompletely elucidated. Mitochondrial dysfunction and impaired mitophagy have been implicated in depression pathogenesis, while SIRT1 has been shown to play a critical role in both depression and mitochondrial regulation. Building on these established associations, this study aimed to investigate the antidepressant mechanisms of running exercise, with particular fucus on mitophagy regulated by SIRT1.

MATERIALS AND METHODS: Chronic social defeat stress (CSDS) model of depression was established in male BALB/c mice to induce depressive-like phenotypes and a 2-week moderate-intensity running exercise protocol was employed as interventions. Depressive-like behaviors and treatment efficacy were assessed through various behavioral tests. Hippocampal neuronal function and mitophagy activity were evaluated using ultra high performance liquid chromatography-tandem mass spectrometry, transmission electron microscopy and western blotting.

KEY FINDINGS: Running exercise significantly ameliorated CSDS-induced depressive-like behaviors and improved hippocampal neuronal function and ultrastructure in CSDS mice. Mechanistically, these beneficial effects were associated with the activation of PINK1-Parkin mediated mitophagy. Furthermore, exercise intervention upregulated hippocampal SIRT1 expression, which was downregulated by CSDS exposure. Notably, pharmacological inhibition of SIRT1 not only abolished the antidepressant effects of running exercise, but also induced depressive-like behaviors in mice and impaired hippocampal PINK1-Parkin mitophagy pathway.

SIGNIFICANCE: The findings demonstrated that running exercise ameliorated CSDS-induced depressive-like behaviors by enhancing hippocampal mitophagy through SIRT1 upregulation and subsequent activation of the PINK1-Parkin pathway. This mechanism promoted the clearance of damaged mitochondria, thereby restoring neuronal function in stressed mice.

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Running exercise alleviates depressive-like behaviors through the activation of PINK1-Parkin mediated mitophagy in mice exposed to chronic social defeat stress

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