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

Mitochondrial dysfunction is a key feature of depressive disorders. This study investigated whether ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUD1) regulates mitochondrial abnormalities contributing to depression in mouse models. Depressive-like phenotypes were induced in wild-type or OTUD1-knockout mice using chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS). Transcriptomic data revealed that OTUD1 expression was selectively upregulated in HPC of both CUMS and LPS mice models. OTUD1 deficiency significantly alleviated depressive-like behaviors, apoptosis and pyroptosis, and inflammatory response through mitophagy. Mechanistically, OTUD1 bound to the MST1/2 at K285/K282 and catalyzed K63-linked deubiquitination through Cys320, enhancing MST1/2 phosphorylation, nuclear translocation, and activation in a TAOK1/2/3-dependent manner. This triggered oxidative stress, apoptosis, pyroptosis, and mitochondrial injury, leading to depressive-like phenotypes. Finally, OTUD1 overexpression exacerbated CUMS or LPS-induced depressive-like phenotypes, whereas MST1/2 inhibition or PR-619 treatment mitigated these effects. These studies have highlighted a novel role of OTUD1 in depressive disorder and identified MST1/2 as a target of OTUD1 in mediating these actions.