Neurobiology of Disease Abnormal Ca Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects

Maintenance of mitochondrial DNA (mtDNA) depends on nuclear-encoded proteins such as mtDNA polymerase (POLG), whose mutations are involved in the diseases caused by mtDNA defects including mutation and deletion. The defects in mtDNA and in intracellular Ca 2 ([Ca 2 ]i ) homeostasis have been reported in bipolar disorder (BD). To understand the relevance of the mtDNA defects to BD, we studied transgenic (Tg) mice in which mutant POLG (mutPOLG) was expressed specifically in neurons. mtDNA defects were accumulated in the brains of mutPOLG Tg mice in an age-dependent manner and the mutant mice showed BD-like behavior. However, the molecular and cellular basis for the abnormalities has not been clarified. In this study, we investigated Ca 2 regulation by isolated mitochondria and [Ca 2 ]i dynamics in the neurons of mutPOLG Tg mice. Mitochondria from the mutant mice sequestered Ca 2 more rapidly, whereas Ca 2 retention capacity and membrane potential, a driving force of Ca 2 uptake, of mitochondria were unaffected. To elucidate the molecular mechanism of the altered Ca 2 uptake, we performed DNA microarray analysis and found that the expression of cyclophilin D (CyP-D), a component of the permeability transition pore, was downregulated in the brains of mutPOLG Tg mice. Cyclosporin A, an inhibitor of CyP-D, mimicked the enhanced Ca 2 uptake in mutant mice. Furthermore, G-protein-coupled receptor-mediated [Ca 2 ]i increase was attenuated in hippocampal neurons of the mutant mice. These findings suggest that mtDNA defects lead to enhancement of Ca 2 uptake rate via CyP-D downregulation and alter [Ca 2 ]i dynamics, which may be involved in the pathogenesis of BD.