Abnormal Ca2+ 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 Ca2+ ([Ca2+]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 Ca2+ regulation by isolated mitochondria and [Ca2+]i dynamics in the neurons of mutPOLG Tg mice. Mitochondria from the mutant mice sequestered Ca2+ more rapidly, whereas Ca2+ retention capacity and membrane potential, a driving force of Ca2+ uptake, of mitochondria were unaffected. To elucidate the molecular mechanism of the altered Ca2+ 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 Ca2+ uptake in mutant mice. Furthermore, G-protein-coupled receptor-mediated [Ca2+]i increase was attenuated in hippocampal neurons of the mutant mice. These findings suggest that mtDNA defects lead to enhancement of Ca2+ uptake rate via CyP-D downregulation and alter [Ca2+]i dynamics, which may be involved in the pathogenesis of BD.
Kubota
Mie
M
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Kasahara
Takaoki
T
Nakamura
Takeshi
T
Ishiwata
Mizuho
M
Miyauchi
Taeko
T
Kato
Tadafumi
T
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017711:Nonlinear Dynamics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D018709:Statistics, Nonparametric
D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; C000631446:PPIF protein, mouse; D043562:Receptors, G-Protein-Coupled; D008734:Methoxyhydroxyphenylglycol; D016572:Cyclosporine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D021983:Cyclophilins; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol