Evolution Meets Disease: Penetrance and Functional Epistasis of Mitochondrial tRNA Mutations

About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur in tRNA genes. Particularly intriguing are those pathogenic tRNA mutations than can reach homoplasmy and yet show very different penetrance among patients. These mutations are scarce and, in addition to their obvious interest for understanding human pathology, they can be excellent experimental examples to model evolution and fixation of mitochondrial tRNA mutations. To date, the only source of this type of mutations is human patients. We report here the generation and characterization of the first mitochondrial tRNA pathological mutation in mouse cells, an m.3739G>A transition in the mitochondrial mt-Ti gene. This mutation recapitulates the molecular hallmarks of a disease-causing mutation described in humans, an m.4290T>C transition affecting also the human mt-Ti gene. We could determine that the pathogenic molecular mechanism, induced by both the mouse and the human mutations, is a high frequency of abnormal folding of the tRNAIle that cannot be charged with isoleucine. We demonstrate that the cells harboring the mouse or human mutant tRNA have exacerbated mitochondrial biogenesis triggered by an increase in mitochondrial ROS production as a compensatory response. We propose that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation. This particular behavior can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both

Significados del concepto medio ambiente en profesores que enseñan geografía en contextos rurales de Chile

In the Chilean Basic Education, the most relevant Geography contents are spatial location, identification of elements of the Landscape, system of cartographic references and Environment. This concept has the greatest presence in the curriculum, lacking a clear conceptualization and dispossessed of relationships with other geographic concepts. An approximation to the concept of the Environment is presented in this text, based on the meanings given by the professors, investigating the relationship between the Environment and the contents of the School Geography. This, in the framework of an interpretative research with an intentional sample of 45 rural teachers from 3 regions of Chile, conducting semi-structured interviews, Data Content Analysis and Theoretical Triangulation. The results show three meanings of Environment: linked to care-recycling-cleaning, synonym of environment and linked to the concern for deterioration. Finally some professors relate Environment with problems that School Geography should teach.En la Educación Básica chilena los contenidos de Geografía más relevantes son ubicación espacial, identificación de elementos del Paisaje, sistema de referencias cartográficas y Medio Ambiente. Este concepto es el de mayor presencia en el currículo, careciendo de una clara conceptualización y desposeído de relaciones con otros conceptos geográficos. Se presenta en este texto una aproximación al concepto Medio Ambiente basada en los significados que dan los/as profesores/as, indagando en las relaciones entre Medio Ambiente y contenidos de la Geografía Escolar. Esto, en el marco de una investigación interpretativa con una muestra intencionada de 45 profesores/as rurales de 3 regiones de Chile, realizando entrevistas semiestructuradas, Análisis de Contenido a los datos y Triangulación Teórica. Los resultados muestran tres significados de Medio Ambiente: ligado al cuidado-reciclaje-limpieza, sinónimo de entorno y vinculado a la preocupación por la degradación. Finalmente, algunos profesores/as relacionan Medio Ambiente con problemáticas que debe enseñar la Geografía Escolar

Reply to "Reactive oxygen species and the segregation of mtDNA sequence variants

2 páginas -- PAGS nros. 571-572Reactive oxygen species and the segregation of mtDNA sequence variantsPeer reviewe

Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants

Common mitochondrial DNA (mtDNA) haplotypes in humans and mice have been associated with various phenotypes, including learning performance and disease penetrance. Notably, no influence of mtDNA haplotype in cell respiration has been demonstrated. Here, using cell lines carrying four different common mouse mtDNA haplotypes in an identical nuclear background, we show that the similar level of respiration among the cell lines is only apparent and is a consequence of compensatory mechanisms triggered by different production of reactive oxygen species. We observe that the respiration capacity per molecule of mtDNA in cells with the NIH3T3 or NZB mtDNA is lower than in those with the C57BL/6J, CBA/J or BALB/cJ mtDNA. In addition, we have determined the genetic element underlying these differences. Our data provide insight into the molecular basis of the complex phenotypes associated with common mtDNA variants and anticipate a relevant contribution of mtDNA single nucleotide polymorphisms to phenotypic variability in humans. © 2006 Nature Publishing Group.Peer Reviewe

Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells

AbstractThe role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondrial enzyme contents, mitochondrial electrical potential (ΔΨm) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti-mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, ΔΨm and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-α, a p53-inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2–5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53-HIF-1α complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O2 level