OTUD1 promotes the progession of depression through mitochondrial damage by targeting MST1/2

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial dysfunction is a hallmark of depressive disorders.
• The role of ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUD1) in depression-related mitochondrial abnormalities is unclear.

Purpose of the Study:

• To investigate the role of OTUD1 in regulating mitochondrial function and its contribution to depressive phenotypes in mouse models.

Main Methods:

• Depressive-like behaviors were induced in wild-type and OTUD1-knockout mice using chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS).
• Transcriptomic analysis was performed on hippocampal samples.
• Mitochondrial function, apoptosis, pyroptosis, and inflammatory markers were assessed.
• Protein-protein interactions and ubiquitination status were analyzed.

Main Results:

• OTUD1 expression was upregulated in mouse models of depression.
• OTUD1 deficiency ameliorated depressive-like behaviors, apoptosis, pyroptosis, and inflammation via mitophagy.
• OTUD1 deubiquitinated and activated MST1/2, leading to oxidative stress, mitochondrial injury, and depressive phenotypes.
• OTUD1 overexpression worsened depressive phenotypes, while MST1/2 inhibition or PR-619 treatment showed protective effects.

Conclusions:

• OTUD1 plays a critical role in mediating mitochondrial dysfunction and depressive phenotypes.
• OTUD1 targets MST1/2, regulating its phosphorylation and activation, thereby influencing cellular stress pathways.
• OTUD1 and MST1/2 represent potential therapeutic targets for depressive disorders.