Glucose-6-phosphate dehydrogenase activity in bipolar disorder and schizophrenia: Relationship to mitochondrial impairment

Abstract Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway that is essential to maintaining cellular redox balance. G6PD is especially plentiful in brain, and its deficiency has been linked to mood and psychotic disorders. We measured G6PD activity spectrophotometrically in four groups of 15 parietal somatosensory association cortex [Brodmann area (BA) 7] tissue samples (N = 60) from individuals with bipolar disorder (BPD); nonpsychotic unipolar major depression (UPD); schizophrenia (SCZ), and controls without psychiatric illness (CON). We report for the first time brain G6PD activity levels in these disorders. G6PD activity did not differ by brain group. In BPD and SCZ brains, however, it correlated significantly and inversely with percent of hexokinase 1 (HK1) in the tissue homogenate mitochondrial fraction as determined previously in another set of tissue samples obtained from the same brains and brain region. The correlation in SCZ brains lost statistical significance after controlling for brain pH. This finding indicates a positive relationship in BPD brains between G6PD activity and HK1 mitochondrial detachment, an indicator of mitochondrial impairment associated with increased mitochondrial generation of reactive oxygen species. We speculate that this relationship could be evidence that G6PD activity is proportionate to and may be a compensatory response to oxidative stress in the BA7 region of BPD brains. Future research should focus on clarifying the relationships among G6PD activity, markers of oxidative stress, brain pH, and evidence of mitochondrial impairment, particularly HK1 mitochondrial detachment, in brains of individuals with G6PD deficiency, BPD and SCZ.