Mitochondrial function in individuals at clinical high risk for psychosis

Abstract

Alterations in mitochondrial function have been implicated in the etiology of schizophrenia. Most studies have investigated alterations in mitochondrial function in patients in which the disorder is already established; however, whether mitochondrial dysfunction predates the onset of psychosis remains unknown. We measured peripheral mitochondrial complex (I-V) function and lactate/pyruvate levels in 27 antipsychotic-naïve individuals at clinical high risk for psychosis (CHR) and 16 healthy controls. We also explored the association between mitochondrial function and brain microglial activation and glutathione levels using a translocator protein 18 kDa [¹⁸F]FEPPA PET scan and ¹H-MRS scan, respectively. There were no significant differences in mitochondrial complex function and lactate/pyruvate levels between CHR and healthy controls. In the CHR group, mitochondrial complex III function (r = -0.51, p = 0.008) and lactate levels (r = 0.61, p = 0.004) were associated with prodromal negative symptoms. As previously reported, there were no significant differences in microglial activation and glutathione levels between groups, however, mitochondrial complex IV function was inversely related to microglial activation in the hippocampus in CHR (r = -0.42, p = 0.04), but not in healthy controls. In conclusion, alterations in mitochondrial function are not yet evident in CHR, but may relate to the severity of prodromal symptoms, particularly negative symptoms.

Figure 1

Mitochondrial complex I–V function in clinical high risk (CHR) for psychosis and healthy controls (HC). Mitochondrial complex (I–V) function was measured in monocyte samples (white blood cells) in a multiplex ELISA assay. Complex function is reported as a percentage against each subject’s individual nicotinamide nucleotide transhydrogenase levels (%NNT); a nucleus-encoded protein present in the inner mitochondrial membrane that is closely related to mitochondrial oxidative phosphorylation. A repeated measures ANOVA was performed to test the effect of group (CHR vs healthy controls) on mitochondrial complex (I–V) function. There were no significant differences in mitochondrial complex (I-V) function between CHR and HC (F_(1,40) = 0.67, p = 0.42).

Figure 2

Association between peripheral mitochondrial complex III function and (a) total SOPS symptom severity score (r = −0.49, p = 0.01) and (b) SOPS negative symptom severity score (r = −0.51, p = 0.008) in clinical high risk (CHR). Lactate levels were measured in plasma using a colormetric L-Lactate Assay Kit, and are reported in nmol/µL. Bivariate correlations were used to investigate the associations between mitochondrial complex function and symptom severity.

Figure 3

Peripheral lactate (a) and pyruvate (b) levels in clinical high risk (CHR) and healthy controls (HC). Lactate and pyruvate levels were measured in plasma using a colormetric L-Lactate Assay Kit and a colormetric Pyruvate Assay Kit, respectively, and are reported in nmol/µL. A univariate analysis of variance was performed to test for differences in lactate and pyruvate between groups. There were no significant differences in lactate or pyruvate levels between CHR and HC (lactate: F_(1,31) = 0.17, p = 0.69; pyruvate: F_(1,31) = 1.31, p = 0.26).

Figure 4

Association between lactate levels and (a) total SOPS symptom severity score (r = 0.54, p = 0.01) and (b) SOPS negative symptom severity score (r = 0.61, p = 0.004) in clinical high risk (CHR). Lactate levels were measured in plasma using a colormetric L-Lactate Assay Kit, and are reported in nmol/µL. Bivariate correlations were used to investigate the associations between lactate levels and symptom severity.

Figure 5

Association between peripheral mitochondrial complex IV function and [¹⁸F]FEPPA total distribution volume (V_T) of hippocampus in clinical high risk (CHR) (r = −0.42, p = 0.04), but not in healthy controls (HC) (r = 0.07, p = 0.82). Mitochondrial complex (I–V) function was measured in monocyte samples (white blood cells) in a multiplex ELISA assay. Complex function is reported as a percentage against each subject’s individual nicotinamide nucleotide transhydrogenase levels (%NNT); a nucleus-encoded protein present in the inner mitochondrial membrane that is closely related to mitochondrial oxidative phosphorylation. [¹⁸F]FEPPA V_T was determined with a 2-tissue compartment model using positron emission tomography (PET). Partial correlations were used to explore the associations between mitochondrial complex function and [¹⁸F]FEPPA V_T, controlling for translocator protein 18 kDa (TSPO) rs6971 polymorphism.