Manco, Rosanna (2013) Molecular alteratons leading to mitochondrial dysfunction in Down Syndrome. [Tesi di dottorato]

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Down Syndrome (DS) is the most frequent autosomal aneuploidy compatible with post-natal life. It has been attributed to the overexpression of chromosome 21 (Hsa21) genes. At least 80 phenotypic signs such as mental retardation, cardiac defects, muscle hypotonia, immunological disorders have been described in DS, however, it is unknown which, and how many, Hsa21 genes are responsible for each sign. Hsa21 trisomy has been associated to mitochondrial dysfunction in different tissues and a global downregulation of nuclear genes encoding mitochondrial enzymes (NEMG) has been demonstrated in heart tissues from DS suggesting that the dysfunction may contribute to the DS phenotype. To establish which correlation there might be between NEMG regulation and mitochondrial function in DS, we undertook molecular, functional and morphological studies on mitochondria in primary lines of fetal fibroblasts (DS-HFF). Hsa21 genes were globally upregulated and NEMG were downregulated in DS-HFF, like in fetal hearts, and a mitochondrial dysfunction was observed. The aim of this work is to understand how alterations in the expression of specific Hsa21 genes might cause mitochondrial dysfunction. Based on literature and prediction databases, the nuclear receptor interacting protein RIP140 and the miRNA let-7c both mapping to Hsa21 were hypothesized to affect oxidative metabolism and mitochondria biogenesis in DS. RIP140 negatively controls the expression of the transcriptional coactivator PGC-1α, a key gene for mitochondrial biogenesis and NEMG expression, which was found downregulated in DS-HFF. To verify the hypothesis that RIP140 overexpression might cause PGC-1α downregulation, RIP140 silencing experiments were performed in DS-HFF demonstrating an inverse correlation between RIP140 and PGC-1α expression and a partial recovery of mitochondrial activity upon downregulation of RIP140 expression. The role of miRNA let-7c in mitochondrial dysfunction was also investigated. Let-7c is upregulated in DS fetal tissues and among its predicted it is included the adenine nucleotide translocator-1 (ANT1), a gene responsible for the ATP/ADP exchange through the mitochondrial inner membrane. We found that in vitro let-7c upregulation caused ANT1 downregulation, suggesting that the upregulation of let-7c, due to primary gene dosage effect, might contribute to the energy deprivation in mitochondrial dysfunction. These findings have potential therapeutic implications based either on in vivo inhibition of RIP140 gene or on the activation of key genes repressed by the overexpression of Hsa21 regulators.

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