Mitochondrial Genomics in Relation to Neuroimaging and Oxygen Dynamics in Youth Bipolar Disorder
Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: Bipolar disorder (BD) is a severe psychiatric disorder affecting approximately 1-3% of youth. Mitochondrial dysfunction is implicated in the neuropathology of BD. Higher circulating cell-free mitochondrial DNA (ccf-mtDNA) and mitochondrial DNA variants, linked to poor mitochondrial health, are associated with BD risk, symptom severity, altered treatment response, and protein dysfunction. In a previous study, we found elevated cerebral blood flow (CBF) among youth with BD, whereas the cerebral metabolic rate of oxygen (CMRO2), which is the rate of oxygen consumption by the brain, was similar to the control group (CG). This suggested abnormal cerebral energy metabolism in which mitochondrial dysfunction may play a role, as the CBF is tightly coupled with the CMRO2 in healthy individuals. Both adults and youth with BD have significantly lower cardiorespiratory (i.e. aerobic) fitness (CRF) compared to CG. The current thesis focuses on markers of mitochondrial dysfunction and investigates ccf-mtDNA, mtDNA variants, and pathogenicity in relation to neurostructural metrics, CBF, CMRO2, and CRF in youth with BD.Serum ccf-mtDNA levels were assayed. Saliva mtDNA was sequenced and an mtDNA functional impact (FI) score was generated. Brain images were collected using 3-Tesla magnetic resonance imaging (MRI). CBF was measured using pseudo-continuous arterial spin labeling. CRF was the average power (watts/kg) within 60-80% of estimated maximum heart rate on a bicycle ergometer. Global estimates for venous blood oxygenation (Yv) were measured using T2-relaxation-under-spin-tagging (TRUST) and CMRO2 was calculated using the Fick principle. For neurostructural metrics, significant ccf-mtDNA-by-diagnosis interaction effects were detected for both surface area and gray matter volume in three frontal and parietal clusters. The regions of interest (ROI) and voxel-wise whole-brain approaches revealed that higher mtDNA pathogenicity was associated with higher CBF in the BD group. Lastly, the appearances of mtDNA variants were associated with CMRO2 differences in the BD group. The current thesis revealed the importance of examining mitochondrial dysfunction in relation to BD early in the course of the illness. Future studies are warranted to further examine the longitudinal association of the current findings.
Source: TSpace (University of Toronto)
Author: Shao, Suyi
Institution: University of Toronto
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132993398