Mitochondrially Mediated Plasticity in the Pathophysiology and Treatment of Bipolar Disorder

Abstract

Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed, including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies, postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD. We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term treatment of the disorder.

Convergent functional genomics of genome‐wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms

“…First, the model that emerges from this work (Fig. 4) is consistent with mood being a function of trophicity [Niculescu, 2005], through energy metabolism [Quiroz et al, 2008] as well as cellular growth and proliferation [Le-Niculescu et al, 2008a]. Speculatively, from an evolutionary standpoint, it may make sense for the organism to react to a favorable environment by activity and expansion, and to an unfavorable environment by inactivity and retraction-the ''mood as a muscle'' model [Niculescu, 2005].…”

Reverse translational strategies for developing animal models of bipolar disorder

“…Although BD is not a traditional mitochondrial disorder, considerable data from diverse sources suggest that altered mitochondrial function may play a role in its pathophysiology and treatment (Kato and Kato, 2000;Quiroz et al, 2008;Stork and Renshaw, 2005). Thus, for example, a number of abnormal magnetic resonance spectroscopy (MRS) findings in BD [including altered N-acetylaspartate (NAA), lactate and highenergy phosphate levels] are compatible with altered mitochondrial function (Kato and Kato, 2000;Quiroz et al, 2008;Stork and Renshaw, 2005).…”

“…Thus, for example, a number of abnormal magnetic resonance spectroscopy (MRS) findings in BD [including altered N-acetylaspartate (NAA), lactate and highenergy phosphate levels] are compatible with altered mitochondrial function (Kato and Kato, 2000;Quiroz et al, 2008;Stork and Renshaw, 2005). Indeed, genetic analyses of mitochondrial DNA (mtDNA) note a significant association between several mtDNA polymorphisms or mutations and BD (Kato et al, 2001;Munakata et al, 2004).…”

Bipolar disorder: from genes to behavior pathways

“…present in the brain of patients with BPD may be associated with alterations in normal mitochondrial function (36). Evidence from microarray, biochemical, neuroimaging, and postmortem studies support the role of mitochondrial dysfunction in BPD (37). In addition to energy production, neuronal mitochondria play an important role in regulating apoptosis, intracellular calcium levels, and synaptic plasticity (24).…”