Increased peripheral blood expression of electron transport chain genes in bipolar depression

Abstract

Objective: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD).

Methods: Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences.

Results: A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p < 0.05, covaried for age and sex). Of these, 559 genes were up-regulated in BPD subjects and 621 were down-regulated. Surprisingly, there was no difference between medicated (n = 11) and unmedicated (n = 9) subjects with BPD for any of these genes. Pathway analysis using GeneGo MetaCore software showed that the most significantly affected pathway was the mitochondrial electron transport chain (ETC). Of the 85 objects (genes or proteins) in this pathway, 22 were up-regulated and 2 down-regulated in subjects with BPD. qRT-PCR confirmed up-regulation of nuclear encoded ETC genes in complexes I, III, IV, and V and, in addition, demonstrated up-regulation of mitochondrially encoded genes in each of these complexes.

Conclusion: These results suggest that increased expression of multiple components of the mitochondrial ETC may be a primary deficit in bipolar depression, rather than an effect of medication.

Fig. 1

Diagram of the mitochondrial electron transport chain showing genes with altered expression in subjects with bipolar disorder (BPD). Complex I (NADH dehydrogenase) catalyzes the removal of two electrons from NADH and transfers them to the electron carrier ubiquinone (Q). The reduced product is ubiquinol (QH2). Complex II (succinate dehydrogenase) catalyzes the conversion of succinate to fumarate and in the process transfers two electrons to ubiquinone via FAD. Complex III catalyzes the removal of two electrons from QH2 and transfers them to two molecules of the electron carrier, cytochrome c. Complex IV removes two electrons from the two molecules of cytochrome c and transfers them to molecular oxygen (O₂), producing water. The proton gradient established by pumping hydrogens across the inner mitochondrial membrane is then utilized by Complex V (ATP synthase) to catalyze the formation of ATP from ADP and Pi. Genes encoding various subunits of complexes I, III, IV, and V that were up-regulated in peripheral blood of subjects with BPD are shown as red hexagons next to the corresponding complex.