Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway (Articolo in rivista)

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  • Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway (Articolo in rivista) (literal)
Anno
  • 2011-01-01T00:00:00+01:00 (literal)
Alternative label
  • Valenti D, Manente GA, Moro L, Marra E, Vacca RA. (2011)
    Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway
    in Biochemical journal (Lond., 1984)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Valenti D, Manente GA, Moro L, Marra E, Vacca RA. (literal)
Pagina inizio
  • 679 (literal)
Pagina fine
  • 688 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 435 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche (CNR), 70126 Bari, Italy. Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, 28100 Novara, Italy. (literal)
Titolo
  • Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway (literal)
Abstract
  • DS (Down's syndrome) is the most common human aneuploidy associated with mental retardation and early neurodegeneration. Mitochondrial dysfunction has emerged as a crucial factor in the pathogenesis of numerous neurological disorders including DS, but the cause of mitochondrial damage remains elusive. In this research, we identified new molecular events involved in mitochondrial dysfunction which could play a role in DS pathogenesis. We analyzed mitochondrial respiratory chain function in DS-HSF (human foetal skin fibroblasts with chromosome 21 trisomy) and found a selective deficit in the catalytic efficiency of mitochondrial complex I. Complex I deficit was associated with a decrease in cAMP-dependent phosphorylation of 18-kDa subunit of the complex, due to a decrease in PKA (protein kinase A) activity related to reduced basal levels of cAMP. Consistently, exposure of DS-HSF to db-cAMP (dibutyryl-cAMP), a membrane-permeable cAMP analog, stimulated PKA activity and consequently rescued the deficit of both the cAMP-dependent phosphorylation and the catalytic activity of complex I; conversely H89, a specific PKA inhibitor, suppressed these cAMP-dependent activations. Furthermore, here we report a three-fold increase in cellular levels of ROS (reactive oxygen species), in particular superoxide anion, mainly produced by DS-HSF mitochondria. ROS accumulation was prevented by db-cAMP-dependent activation of complex I suggesting its involvement in ROS production. Taken together, these results suggest that the drastic decrease in basal cAMP levels observed in DS-HSF participates to complex I deficit and overproduction of ROS by DS-HSF mitochondria. (literal)
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