Targeting mitochondrially mediated plasticity to develop improved therapeutics for bipolar disorder

Abstract

Introduction Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology. Areas covered This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca2+) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca2+ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients. Expert opinion Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

“…Although accumulating evidence points towards mitochondrial dysfunction in psychiatric disorders (Manji et al, 2012), the therapeutic potential of mitochondrial targeting has only been recently highlighted for bipolar disorder (de Sousa et al, 2014) and autism (Ghanizadeh et al, 2013) and has never been tested in vivo. Our study is the first in vivo application of selective mitochondrial targeting in the context of psychiatric disorders.…”

Bcl-2 associated with severity of manic symptoms in bipolar patients in a manic phase

“…Bcl-2 might regulate Ca 2þ signals by interacting with the inositol 1,4,5-trisphosphate receptor to provoke cell survival (Distelhorst and Bootman, 2011). In addition, mitochondrial dysfunction could affect apoptosis, Ca 2þ signaling and oxidative stress in bipolar disorder (de Sousa et al, 2014). Therefore, mitochondrial dysfunction might influence Bcl-2 protein levels in bipolar disorder.…”

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

“…Mitochondrial dysfunction has been implicated in BD [7,8,9,10]. 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].…”

“…Research on the role of the mitochondrial genome in BD risk has revealed candidate associations with mitochondrial point mutations, deletions, haplogroups (subjects sharing the same maternal ancestral haplotypes), and copy number variations [19,20,21,22]. For instance, the rare mtDNA mutation 3644T>C was found to be associated with BD [7,19]. In addition, various mitochondrial single-nucleotide polymorphisms (mtSNPs) have been proposed to be associated with BD [19,22,23,24].…”