14 de febrero 2014. Seminario New mechanistic insights into the pathogenesis of MELAS disease
El Seminario que se realizará el próximo 14 de febrero a las 13 horas en el Salón de Actos del Centro de Investigación Príncipe Felipe, será impartido por Salvador Meseguer.
The molecular mechanisms underlying mitochondrial (mt) human diseases associated with defects in mt-tRNA modification like MELAS still remain unresolved. MELAS syndrome is caused by mutations in the mt-DNA affecting mt-tRNALeu(UUR). Although the mutation effect has been associated with a repertory of mechanisms, impaired tRNA recognition by nucleus-encoded enzymes involved in the post-transcriptional modification of the wobble uridine seems to be a critical factor in the evolution to mitochondrial dysfunction.
Wobble modifications are thought to contribute to translational accuracy and/or efficiency; therefore, modification defects may lead to a defective translation of mt-DNA-encoded proteins and, accordingly, to functional perturbations of the OXPHOS system. However, several studies in MELAS and similar diseases suggest that defects of mitochondrial protein synthesis cannot fully explain the mitochondrial dysfunction manifested. We tested the hypothesis that regulation of the mt-tRNA modification enzymes may participate in the pathogenic mechanisms underlying these diseases. In fact, we found that wobble modification defects in MELAS are accompanied by an unexpected reduction in the steady-state levels of such enzymes.
So far, nothing was known on the regulatory mechanisms controlling these proteins, which now appear as interesting baits to follow the cross-talk between mitochondrial and nuclear genomes in this pathology. Since ROS is increased in MELAS cells and these species have been hypothesized to cause a microRNA-mediated response in mtDNA disorders, we wondered whether under-expression of the tRNA modifying enzymes in MELAS could be a consequence of a microRNA-directed regulation. Our work demonstrates that microRNA-9/9* is over-expressed through the ROS/NF-kB signaling pathway in cells carrying a MELAS mutation, acting as a negative post-transcriptional regulator of the modifying enzymes and thus contributing to the pathogenic effect.
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