Polymorphism in Murine mtATP8 Gene Correlates with Decreased Reactive Oxygen Species in Aging Hematopoietic Cells

Roolf, Catrin; Kretzschmar, Christin; Timmer, Katrin; Sekora, Anett; Knübel, Gudrun; Escobar, Hugo Murua; Fuellen, Georg; Ibrahim, Saleh M.; Tiedge, Markus; Baltrusch, Simone; Müller, Sarah; Köhling, Rüdiger; Junghanß, Christian

doi:10.21873/invivo.10991

Cited by 2 publications

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“…Since mtDNA mutations affect oxidative phosphorylation, we wanted to characterize the conplastic mtNOD mouse with respect to reactive oxygen species (ROS) production and mitochondrial dynamic network formation known as fusion‐fission processes. Then, we asked for functional consequences of mitochondrial dysfunction in this model by assessing learning and memory as well as survival.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice

et al. 2018

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Aim: Mitochondrial DNA (mtDNA) mutations can negatively influence lifespan and organ function. More than 250 pathogenic mtDNA mutations are known, often involving neurological symptoms. Major neurodegenerative diseases share key etiopathogenetic components ie mtDNA mutations, mitochondrial dysfunction and oxidative stress. Methods: Here, we characterized a conplastic mouse strain (C57BL/6 J-mtNOD) carrying an electron transport chain complex IV mutation that leads to an altered cytochrome c oxidase subunit III. Since this mouse also harbours adenine insertions in the mitochondrial tRNA for arginine, we chose the C57BL/6 J-mtMRL as control strain which also carries a heteroplasmic stretch of adenine repetitions in this tRNA isoform. Results: Using MitoSOX fluorescence, we observed an elevated mitochondrial superoxide production and a reduced gene expression of superoxide dismutase 2 in the 24-month-old mtNOD mouse as compared to control. Together with the decreased expression of the fission-relevant gene Fis1, these data confirmed that the ageing mtNOD mouse had a mitochondrial dysfunctional phenotype. On the functional level, we could not detect significant differences in synaptic long-term potentiation, but found a markedly poor physical constitution to perform the Morris water maze task at the age of 24 months. Moreover, the median lifespan of mtNOD mice was significantly shorter than of control animals. Conclusion: Our findings demonstrate that a complex IV mutation leads to mitochondrial dysfunction that translates into survival. K E Y W O R D Scomplex IV mutation, FIS1, lifespan, mitochondrial DNA, reactive oxygen species, SOD2

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Section: Introductionmentioning

confidence: 99%

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice

et al. 2018

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Combination of mitochondrial tRNA and OXPHOS mutation reduces lifespan and physical condition in aged mice

Reichart

Mayer

Tokay

et al. 2017

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Mutations in the mitochondrial DNA (mtDNA) are widely known to impact on lifespan and tissue integrity. For example, more than 250 pathogenic mtDNA mutations are known, many of which lead to neurological symptoms. In addition, major neurodegenerative diseases share key components of their etiopathogenesis with regard to mtDNA mutations, mitochondrial dysfunction and oxidative stress. In our study we used a set of conplastic mouse models carrying stable point mutations in mitochondrial genes of transfer RNA (tRNA) and oxidative phosphorylation (OXPHOS)-proteins. We analyzed the impact of these mutations on complex traits like lifespan, learning and memory in the ageing process. The combination of both point mutations in the OXPHOS complex IV gene and adenine insertions in the mitochondrially encoded tRNA arginine (tRNA-Arg) gene (mt-Tr) leads to an agedependent phenotype with elevated mitochondrial superoxide production in the neocortex. Mice with this combination of tRNA and OXPHOS mutations show significantly reduced lifespan and poor physical constitution at the age of 24 months, whereas single point mutations in OXPHOS or mt-tRNA(Arg) do not have this impact. Therefore, we suggest a synergistic effect of these mutations.not peer-reviewed)

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Polymorphism in Murine mtATP8 Gene Correlates with Decreased Reactive Oxygen Species in Aging Hematopoietic Cells

Cited by 2 publications

References 34 publications

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice

Mitochondrial complex IV mutation increases reactive oxygen species production and reduces lifespan in aged mice

Combination of mitochondrial tRNA and OXPHOS mutation reduces lifespan and physical condition in aged mice

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