Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder.

Laboratory of Molecular Pathophysiology, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 8.68). 02/2008; 33(11):2551-65. DOI: 10.1038/sj.npp.1301671
Source: PubMed

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.

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    ABSTRACT: Mitochondria are unique and important organelles in terms of energy production for the eukaryotic cell. Through complexes of the electron transport chain embedded in the mitochondrial membrane, the cell is able produce large amounts of ATP. Mitochondria posses their own genome, some of which encodes for the subunits of these protein complexes. From the comorbidity of psychotic symptoms seen in those with mitochondrial disorders, the change in efficiency of cellular respiration has started to emerge as a target for research for understanding the mechanisms and potential therapeutic approaches in mental disorders. Schizophrenia is the hallmark of psychotic diseases and its diverse symptoms have been implicated to have its primary effects in the mesolimbic and mesocortical pathways in the brain. Mitochondrial concentrations in these areas and mutations within the mitochondrial genome are an active area of research. Additionally, the effects of mood stabilizers and antipsychotics in terms of oxidative phosphorylation have been examined in proteomics, DNA and RNA microarray technology, and neuroimaging to name a few. In this article, we make an attempt to discuss and analyze the effects of mutations in the mitochondrial genome with respect to electron transport chain and cellular respiration in individuals affected with schizophrenia.


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