NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.
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.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
Antonella
A
Izzo
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
Rosanna
R
Manco
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
Ferdinando
F
Bonfiglio
Institute of Experimental Endocrinology and Oncology, National Research Council, Naples 80131, Italy.
Gaetano
G
Calì
Institute of Experimental Endocrinology and Oncology, National Research Council, Naples 80131, Italy.
Tiziana
T
De Cristofaro
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara 44100, Italy.
Simone
S
Patergnani
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
Rita
R
Cicatiello
Department of Clinical and Experimental Medicine, University of Foggia, Foggia 71100, Italy.
Rosella
R
Scrima
Institute of Experimental Endocrinology and Oncology, National Research Council, Naples 80131, Italy.
Mariastella
M
Zannini
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara 44100, Italy.
Paolo
P
Pinton
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy anconti@unina.it.
Anna
A
Conti
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
Lucio
L
Nitsch
D037881:Aborted Fetus / Q000166:cytology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000378:metabolism*; D005347:Fibroblasts; D050259:Genes, Mitochondrial / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014314:Trisomy
D048868:Adaptor Proteins, Signal Transducing; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D002118:Calcium