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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-1α  or  PPARGC1A )—a key modulator of mitochondrial function—and of several nuclear-encoded mitochondrial genes (NEMGs). Re-analysis of publicly available expression data related to manipulation of chromosome 21 (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-1α . To establish whether  NRIP1  overexpression in DS downregulates both  PGC-1α  and NEMGs, thereby causing mitochondrial dysfunction, we used siRNAs to decrease  NRIP1  expression in trisomic human fetal fibroblasts. Levels of  PGC-1α  and NEMGs were increased and mitochondrial function was restored, as shown by reactive oxygen species decrease, adenosine 5′-triphosphate (ATP) production and mitochondrial activity increase. These findings indicate that the Hsa21 gene  NRIP1  contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the  NRIP1-PGC-1α  axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS.

NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome