NRIP1/RIP140 siRNA-mediated Attenuation Counteracts Mitochondrial Dysfunction In Down Syndrome

作者：Izzo Antonella; Manco Rosanna; Bonfiglio Ferdinando; Cali Gaetano; de Cristofaro Tiziana; Patergnani Simone; Cicatiello Rita; Scrima Rosella; Zannini Mariastella; Pinton Paolo; Conti Anna^*; Nitsch Lucio

来源：Human Molecular Genetics, 2014, 23(16): 4406-4419.

DOI：10.1093/hmg/ddu157

Mitochondrial dysfunction, which is consistently observed in Down syndrome (DS) cells and tissues, might contribute to the severity of the DS phenotype. Our recent studies on DS fetal hearts and fibroblasts have suggested that one of the possible causes of mitochondrial dysfunction is the downregulation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha or PPARGC1A)-a key modulator of mitochondrial function-and of several nuclear encoded mitochondrial genes (NEMGs). Reanalysis of publicly available expression data related to manipulation of Hsa21 genes suggested the nuclear receptor interacting protein 1 (NRIP1 or RIP140) as a good candidate Hsa21 gene for NEMG downregulation. Indeed, NRIP1 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PGC-1 alpha. To establish whether NRIP1 over-expression in DS downregulates both PGC-1 alpha and NEMGs, thereby causing mitochondrial dysfunction, we used siRNAs to decrease NRIP1 expression in trisomic human fetal fibroblasts. Levels of PGC-1 alpha and NEMGs were increased and mitochondrial function was restored, as shown by ROS decrease, ATP production and mitochondrial activity increase. %26lt;br%26gt;These findings indicate that the Hsa21 gene NRIP1 contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the NRIP1-PGC-1 alpha axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS.

• 出版日期2014-8-15