Greater Mitochondrial DNA Pathogenicity is Associated with Greater Regional Cerebral Blood Flow in Youth Bipolar Disorder

Mitochondrial dysfunction is implicated in the neuropathology of bipolar disorder (BD). Mitochondrial DNA (mtDNA) variants are associated with anomalous cerebral energy metabolism and with increased risk for BD. Little is known about the relevance of mtDNA to cerebral blood flow (CBF) in BD. Participants included 101 youth (BD, n = 56; Control group, n = 45; ages 13–20). The Miseq platform was used to sequence saliva mtDNA. The mtDNA-Server pipeline was used for variant calling and annotation. mtDNA common variants (i.e. minor allele frequency larger than 5%) were included in the analyses due to sample size. We generated an mtDNA variant functional impact (FI) score by performing functional analysis using Mutserve and summing across the MutPred, Selection Score, and MitoTool algorithms. CBF was measured using pseudo-continuous arterial spin labeling magnetic resonance imaging. Region of interest (ROI) analyses examined FI scores in relation to CBF in the anterior cingulate cortex (ACC) and global gray matter, controlling for age and sex. Voxel-based analyses were also conducted. In ROI analyses, higher mtDNA FI score was associated with higher ACC CBF in the overall sample (β = 0.20, p  = 0.045). In voxel-based analyses, higher mtDNA FI score was associated with higher CBF in regions within the basal ganglia, frontal and parietal lobe, and cingulate within the overall sample and within the BD group. This study found that higher mtDNA FI score, putatively reflecting mtDNA pathogenicity, was associated with higher regional CBF among youth. Present findings add to the evidence that elevated CBF may be a compensatory mechanism in youth with BD.