Altered intracellular
calcium levels are a consistent finding in studies of
bipolar disorder, and recent studies point to the role of
mitochondrial dysfunction, leading to the possibility that mitochondrial
calcium dysregulation is involved in the pathophysiology of the disease. Although the mitochondrion is a key organelle for
calcium accumulation, initial calcium signaling studies in
bipolar disorder did not focus on the role of mitochondria. Later, neuroimaging and molecular genetic studies suggested the possibility that altered mitochondrial
calcium regulation due to
mitochondrial DNA (
mtDNA) polymorphisms/mutations might be involved in the pathophysiology of
bipolar disorder. Recent studies show that certain
mtDNA polymorphisms alter mitochondrial
calcium levels. Mutant
mtDNA polymerase (Polg) transgenic mice carrying
mtDNA mutations in forebrain cells show an increased
calcium uptake rate in isolated mitochondria. This was found to be mediated by downregulation of
cyclophilin D, a component of the
mitochondrial permeability transition pore. In addition, agonist-stimulated
calcium response is attenuated in hippocampal neurons of these transgenic mice. The finding that
mtDNA polymorphisms and mutations affect mitochondrial
calcium regulation supports the idea that mitochondrial
calcium dysregulation may be involved in the pathophysiology of
bipolar disorder. In this review, the history and recent findings of studies elucidating the role of mitochondrial calcium signaling in
bipolar disorder are summarized.