Mollo, Nunzia (2018) Mitochondrial alterations in Down syndrome: molecular mechanisms and therapeutic opportunities. [Tesi di dottorato]

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Increasing evidence suggests that the mitochondrial dysfunction represents a hallmark in Down syndrome (DS) and that it can play a role in the pathogenesis of DS. Impaired expression/activity of PGC-1α, a crucial modulator of mitochondrial biogenesis and functions, is emerging as a common underlying cause of mitochondrial dysfunction in several diseases. The analysis of molecular mechanisms responsible for the DS phenotype identified in the over-expression of the chromosome 21 repressor gene NRIP1/RIP140 a cause of the decreased in the expression and activity of PGC-1α and of several mitochondria-related genes. We demonstrated that by silencing NRIP1 in trisomic cells it was possible to counteract the mitochondrial alterations observed in these cells, including irregular mitochondrial dynamics together with defects in the fission-fusion machinery. On this basis we tested the hypothesis that the induction of PGC-1α and of its downstream pathways might be able to reverse the mitochondrial dysfunction in DS. To this end we induced PGC-1α in trisomic fetal fibroblasts using two strategies: i) we used metformin, which stimulates PGC-1α through AMPK and SIRT1 activity; ii) we activated PGC-1α through the PPAR agonist pioglitazone. We demonstrated that both drugs were able to induce the PGC-1α pathway in trisomic cells. Both strategies stimulated respiratory capacity and increased ATP levels, while ROS production decreased. Most interestingly, both drugs affected mitochondrial dynamics promoting the formation of a mitochondrial network with branched and elongated tubular morphology. Accordingly, the expression of genes involved in the fission-fusion machinery, namely OPA1, Mitofusins and DRP-1, was modulated by either treatment, though the two drugs elicited different changes. These results indicate that the induction of PGC-1α counteracts the mitochondrial dysfunction in DS cells stimulating the mitochondrial biogenesis and promoting the formation of a mitochondrial network. We also investigated the role of chromosome 21 miRNAs in promoting mitochondrial alterations in DS. We put special attention to let-7c-5p, miR-155-5p and miR-99a-5p which are up-regulated in human fetal hearts. The study of their targets down-regulated in DS fetal hearts and involved in mitochondrial function identified the ATP translocator the SLC25A4/ANT1 as a let-7c-5p target candidate for mitochondrial anomalies. Taken all together these results indicate that unraveling the molecular mechanisms that underlie mitochondrial dysfunction in DS paves the way to new therapeutic approaches to counteract DS phenotypic traits and/or to prevent DS associated pathologies.

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