X-Linked USP11 Drives Depression-Like Behaviors by Stabilizing CK2α and Disrupting Mitochondrial Function

To explore the role and mechanism of X-linked USP11 in mitochondrial dysfunction associated with depression.

USP11 knockout mice and USP11 overexpression mice in the prefrontal cortex were constructed, and the role of USP11 in mitochondrial dysfunction in depression was evaluated by behavioral tests and quantitative analysis of mitochondrial function changes in the prefrontal cortex. The interaction protein CK2α of USP11 in depression was identified by IP-MS, and the role of CK2α was confirmed by using the selective inhibitor CX4945. The direct effects of USP11 and CK2α on mitochondrial function were further verified by using primary neurons.

USP11 mediates depression-like behaviors and impairs mitochondrial function in mice. Mechanistically, USP11 binds to and deubiquitinates CK2α, stabilizing its protein level and promoting mitochondrial dysfunction. The selective inhibitor CX4945 reverses the impairment of neuronal mitochondrial function by CK2α.

This study demonstrates that USP11 directly binds to and deubiquitinates CK2, affecting mitochondrial function in the mPFC and leading to depressive-like behaviors in mice.