Mitochondria dysfunction and bipolar disorder: From pathology to therapy

Abstract

Bipolar disorder (BD) is one of the major psychiatric diseases in which the impairment of mitochondrial functions has been closely connected or associated with the disease pathologies. Different lines of evidence of the close connection between mitochondria dysfunction and BD were discussed with a particular focus on (1) dysregulation of energy metabolism, (2) effect of genetic variants, (3) oxidative stress, cell death and apoptosis, (4) dysregulated calcium homeostasis and electrophysiology, and (5) current as well as potential treatments targeting at restoring mitochondrial functions. Currently, pharmacological interventions generally provide limited efficacy in preventing relapses or recovery from mania or depression episodes. Thus, understanding mitochondrial pathology in BD will lead to novel agents targeting mitochondrial dysfunction and formulating new effective therapy for BD.

Keywords: Anaerobic respiration; Apoptosis; Energy; Gene variant; Metabolism; Oxidative phosphorylation; Oxidative stress.

Fig. 1

Overview of mitochondrial dysfunction in bipolar disorder. In BD cells, TCA (or Kreb cycle) is disturbed, and its metabolic profile switches from OXPHOS to aerobic glycolysis and lactate production, with a concomitant decreased intracellular pH level. Decreased OXPHOS and reduced UCP2 also induce ROS accumulation leading to subcellular changes and apoptosis. Accumulation of unfolded proteins causes ER stress that subsequently can induce apoptosis. Excess calcium influx leads to high levels of intracellular calcium concentration. Lithium attenuates neuronal Ca²⁺ entry and subsequently normalises the hyperexcitable neurones. ROS - reactive oxygen species; UCPs - uncoupling proteins; ER – endoplasmic reticulum; OXPHOS – oxidative phosphorylation; mtDNA – mitochondrial DNA; TCA - tricarboxylic acid cycle; GPCR – G protein-coupled receptor; IP3 – inositol triphosphate. The organelles within the cell image were created using Servier Medical Art templates at https://smart.servier.com, which are licensed under a Creative Commons Attribution 3.0 Unported License.

Fig. 2

A summary of mitochondrial dysfunctions in bipolar disorder and the potential therapeutic options.