Analysis of entire physiological roles of mammalian mtDNA by generation of mice carrying various pathogenic mutations

科学研究費助成事業(科学研究費補助金)研究成果報告書：基盤研究(S)2007-2011課題番号：1910000

Demonstration of deterministic and high fidelity squeezing of quantum information

By employing at recent proposal (R. Filip, P. Marek and U.L. Andersen, Phys. Rev. A {\bf 71}, 042308 (2005) \cite{Filip05.pra}), we experimentally demonstrate a universal, deterministic and high-fidelity squeezing transformation of an optical field. It relies only on linear optics, homodyne detection, feedforward and an ancillary squeezed vacuum state, thus direct interaction between a strong pump and the quantum state is circumvented. We demonstrate three different squeezing levels for a coherent state input. This scheme is highly suitable for the fault-tolerant squeezing transformation in a continuous variable quantum computer.Comment: 5 pages, 4 figure

Association of predicted pathogenic mutations in mitochondrial ND genes with distant metastasis in NSCLC and colon cancer

Cancer cells have more mutations in their mitochondrial DNA (mtDNA) than do normal cells, and pathogenic mutations in the genes encoding mitochondrial NADH dehydrogenase (ND) subunits have been found to enhance the invasive and metastatic ability of various tumour cells in animal experiments. However, it is unknown whether single-nucleotide variants (SNVs) of the ND genes that decrease complex I activity are involved in distant metastasis in human clinical samples. Here, we demonstrated the enhancement of the distant metastasis of Lewis lung carcinoma cells by the ND6 13885insC mutation, which is accompanied by the overexpression of metastasis-related genes, metabolic reprogramming, the enhancement of tumour angiogenesis and the acquisition of resistance to stress-induced cell death. We then sequenced ND genes in primary tumour lesions with or without distant metastases as well as metastatic tumour lesions from 115 patients with non-small cell lung cancer (NSCLC) and colon cancer, and we subsequently selected 14 SNVs with the potential to decrease complex I activity. Intriguingly, a significant correlation was observed (P < 0.05 by Chi-square test) between the incidence of the selected mutations and distant metastasis. Thus, these results strongly suggest that pathogenic ND gene mutations participate in enhancing distant metastasis in human cancers

Mitochondrial DNA Mutations Regulate Metastasis of Human Breast Cancer Cells

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Administration of an Antioxidant Prevents Lymphoma Development in Transmitochondrial Mice Overproducing Reactive Oxygen Species

Because of the difficulty to exclude possible involvement of nuclear DNA mutations, it has been a controversial issue whether pathogenic mutations in mitochondrial DNA (mtDNA) and the resultant respiration defects are involved in tumor development. To address this issue, our previous study generated transmitochondrial mice (mito-mice-ND613997), which possess the nuclear and mtDNA backgrounds derived from C57BL/6J (B6) strain mice except that they carry B6 mtDNA with a G13997A mutation in the mt-Nd6 gene. Because aged mito-mice-ND613997 simultaneously showed overproduction of reactive oxygen species (ROS) in bone marrow cells and high frequency of lymphoma development, current study examined the effects of administrating a ROS scavenger on the frequency of lymphoma development. We used N-acetylcysteine (NAC) as a ROS scavenger, and showed that NAC administration prevented lymphoma development. Moreover, its administration induced longevity in mito-mice-ND613997. The gene expression profiles in bone marrow cells indicated the upregulation of the Fasl gene, which can be suppressed by NAC administration. Given that natural-killer (NK) cells mediate the apoptosis of various tumor cells via enhanced expression of genes encoding apoptotic ligands including Fasl gene, its overexpression would reflect the frequent lymphoma development in bone marrow cells. These observations suggest that continuous administration of an antioxidant would be an effective therapeutics to prevent lymphoma development enhanced by ROS overproduction

Mitochondrial DNA with a Large-Scale Deletion Causes Two Distinct Mitochondrial Disease Phenotypes in Mice

Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice

Selection of Rodent Species Appropriate for mtDNA Transfer to Generate Transmitochondrial Mito-Mice Expressing Mitochondrial Respiration Defects

Previous reports have shown that transmitochondrial mito-mice with nuclear DNA from Mus musculus and mtDNA from M. spretus do not express respiration defects, whereas those with mtDNA from Rattus norvegicus cannot be generated from ES cybrids with mtDNA from R. norvegicus due to inducing significant respiration defects and resultant losing multipotency. Here, we isolated transmitochondrial cybrids with mtDNA from various rodent species classified between M. spretus and R. norvegicus, and compared the O2 consumption rates. The results showed a strong negative correlation between phylogenetic distance and reduction of O2 consumption rates, which would be due to the coevolution of nuclear and mitochondrial genomes and the resultant incompatibility between the nuclear genome from M. musculus and the mitochondrial genome from the other rodent species. These observations suggested that M. caroli was an appropriate mtDNA donor to generate transmitochondrial mito-mice with nuclear DNA from M. musculus. Then, we generated ES cybrids with M. caroli mtDNA, and found that these ES cybrids expressed respiration defects without losing multipotency and can be used to generate transmitochondrial mito-mice expressing mitochondrial disorders

Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice

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Nuclear but Not Mitochondrial DNA Involvement in Respiratory Complex I Defects Found in Senescence-Accelerated Mouse Strain, SAMP8

This study determined pathogenicity of an A11181G mtDNA mutation found in a senescence-accelerated mouse strain, SAMP8. The mutation was at a highly conserved site of the mt-Nd4 gene, which encodes one of the respiratory complex I subunits. The young SAMP8 expressed reduced complex I activity, which is controlled by both nuclear and mitochondrial DNA (mtDNA). To exclude the nuclear effects, we isolated transmitochondrial cybrids that share the same nuclear background, but possess mtDNA with or without the mutation. The cybrids showed normal respiratory function irrespective of whether their mtDNA possessed the mutation or not, suggesting that the A11181G mutation is not responsible for respiration defects found in SAMP8

ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis

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