Title of project

Targeting mitochondrial metabolism in mental disorders

Abstract

Mitochondrial dysfunction is hypothesized as a key factor in the pathogenesis of 1) psychiatric disorders and 2) their comorbid cardiometabolic disorders. To date, research has almost exclusively focused on peripheral tissues or post-mortem brain samples, and no large-scale longitudinal studies have been done nor have direct investigations of mitochondrial function in the cerebrospinal fluid (CSF) of psychiatric patients. Our project aims to address this gap by conducting the largest study ever, utilizing both nationwide cohort data and clinical data. We will be the first to use the Danish Nationwide Registers and the iPSYCH cohort to investigate mitochondrial dysfunction and its association with mental disorders and comorbid cardiometabolic disorders. Further, we will be the first to directly measure mitochondrial DNA (mtDNA) in the CSF of psychiatric patients in collaboration with Dr. Martin Picard at Columbia University, an expert in mitochondria and stress biology.

Our specific aims include: (1) determining if individuals with primary mitochondrial disorders are at increased risk for developing mental disorders and comorbid cardiometabolic disorders using Danish nationwide registers; (2) analyzing genetic markers of mitochondrial function in mental disorder cases compared to controls, with a focus on the mediation effects of stress, using genomewide interaction studies; (3) comparing CSF lactate levels, a known marker of mitochondrial dysfunction, and their correlation with subsequent diagnoses of mental disorders and comorbid cardiometabolic disorders using Danish nationwide registers; and (4) examining mitochondrial function in the CSF and blood of 350 patients with recent-onset depression or psychotic disorders, and 175 healthy controls at baseline and at 1 year follow up for longitudinal correlations.

Our expected outcomes include a deeper understanding of the role of mitochondrial dysfunction in the development of mental disorders and its relation to comorbid cardiometabolic disorders. We also anticipate to identify novel biomarkers and potentially future therapeutic targets. We anticipate using these novel biomarkers to guide future interventions aimed at reducing the burden of psychiatric and comorbid cardiometabolic diseases.