Catechol-

Dysregulated dopamine (DA) signaling and redox homeostasis contributes to multiple neuropsychiatric and neurodegenerative disorders. Polymorphisms that influence the activity of catechol-O-methyltransferase (COMT), an enzyme critical for degrading DA in the dorsolateral prefrontal cortex, have been implicated in behavioral and neuropsychiatric alterations associated with schizophrenia (SCZ). Adverse neuropsychiatric effects have also been reported in Parkinson's disease (PD) patients administered COMT inhibitors in combination with other DA-enhancing therapies. COMT exists as two isoforms: a soluble short isoform (S-COMT) and a membrane-bound long isoform (MB-COMT). These variants differ in their N-terminal domains, with MB-COMT being the predominant brain isoform. Here, unbiased proteomic and biochemical analyses show that genetic loss of MB-COMT disrupts DA signaling and perturbs pathways governing synaptic and mitochondrial function, iron and copper homeostasis, and redox balance. Limited proteolysis mass spectrometry (LiP-MS) further revealed that MB-COMT deficiency triggers widespread protein structural alterations, a molecular event commonly occurring in neurodegenerative conditions but not as well studied in neuropsychiatric diseases. Our results show that MB-COMT is a molecular hub that connects multiple cellular pathways whose differential dysregulation underlies the pathophysiology of complex neuropsychiatric diseases such as SCZ. Thus, MB-COMT is identified as a key regulator of brain DA biology, loss of which activates cellular stress response pathways, revealing potential targets for therapeutic intervention.