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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Depression is a complex disorder often linked to mitochondrial dysfunction.
• The role of specific deubiquitinating enzymes, like USP11, in this process remains unclear.

Purpose of the Study:

• To investigate the function and mechanism of X-linked USP11 in depression-related mitochondrial dysfunction.
• To identify key interacting proteins involved in USP11's mechanism.

Main Methods:

• Generated USP11 knockout and overexpression mouse models in the prefrontal cortex.
• Assessed depression-like behaviors and mitochondrial function.
• Identified USP11 interacting proteins using immunoprecipitation-mass spectrometry (IP-MS).
• Utilized a CK2α inhibitor (CX4945) and primary neuron cultures to confirm mechanisms.

Main Results:

• USP11 deficiency ameliorated depression-like behaviors and improved mitochondrial function.
• USP11 was found to bind and deubiquitinate CK2α, stabilizing its protein levels.
• This stabilization promoted mitochondrial dysfunction and depression-like phenotypes.
• Inhibition of CK2α reversed USP11-induced mitochondrial impairment.

Conclusions:

• USP11 directly interacts with and deubiquitinates CK2α.
• This interaction destabilizes CK2α, leading to mitochondrial dysfunction in the medial prefrontal cortex (mPFC).
• USP11-mediated mitochondrial dysfunction contributes to depression-like behaviors in mice.