Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder

Abstract

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

“…Increased lipid peroxidation has been noted in the myelin fraction in individuals with BD. 35 Oligo dendrocyte precursor cells (OPCs) present during develop ment typically differentiate into mature oligodendrocytes during myelination; however, a population of OPCs persists in the adult brain. 36 In response to demyelination signals, adult OPCs proliferate and differentiate into mature oligo dendrocytes capable of remyelination.…”

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

“…The mtSNP rs3088309 (merged into rs527236209) located in the Mt-CytB gene, is a missense variant that causes an amino acid change from leucine (major allele) to isoleucine (minor allele) at position 236. Given the relevance of the Mt-CytB gene to the electron transport chain, any mutation in this gene potentially contributes reactive oxygen species, which has been shown to be elevated in BD [14,15]. Being essential for electron transport chain, the mutations in CytB rs3088309 and ND4 rs3915952 might leave neurons more vulnerable to genetic and environmental risk factors.…”

“…The energy dysregulation has been characterized by increased reactive oxygen species production, decreased mitochondrial complex subunits in the brain, ATP-dependent proteasome degradation, and an increase in lactate with a corresponding decreased intracellular pH [11,12,13,14,15,16]. Because mitochondrial DNA (mtDNA) encodes a number of mitochondrial proteins, it has been hypothesized that inherited variation in the mitochondrial genome may affect mitochondrial dysfunction and thus BD risk.…”

Biomarkers for bipolar disorder: current insights

“…118 Alterations in mitochondrial functionality are associated with increased production of ROS that can induce oxidative stress and lead to redox modulations of macromolecules. 119,120 Alterations to proteins, lipids, and DNA induced by mitochondrial dysfunction were found in postmortem brain samples, [121][122][123][124] as well as in peripheral blood cells, 68,122,125,126 from patients with BD. Changes in mitochondrial function and redox modulation patterns were strongly associated with lipid peroxidation and DNA aberrations, which include changes in methylated and oxidized DNA.…”