Chronic Pro-oxidative State and Mitochondrial Dysfunctions are more Pronounced in Fibroblasts from Down Syndrome Foeti with Congenital Heart Defects

Trisomy of chromosome 21 is associated to congenital heart defects in ∼50% of affected newborns. Transcriptomeanalysisofheartsfromtrisomichumanfoetidemonstratedthatgenesinvolvedinmitochondrial function are globally downregulated with respect to controls, suggesting an impairment of mitochondrial function.Weinvestigated herethepropertiesofmitochondriainfibroblasts fromtrisomicfoetiwithandwithoutcardiac defects. Together with the upregulation of Hsa21 genes and the downregulation of nuclear encoded mitochondrial genes, an abnormal mitochondrial cristae morphology was observed in trisomic samples. Furthermore,impairmentof mitochondrial respiratory activity,specific inhibitionof complex I,enhancedreactive oxygen species production and increased levels of intra-mitochondrial calcium were demonstrated. Seemingly, mitochondrial dysfunction was more severe in fibroblasts from cardiopathic trisomic foeti that presented a more pronounced pro-oxidative state. The data suggest that an altered bioenergetic background intrisomy21foetimightbeamongthefactorsresponsibleforamoreseverephenotype.Sincethemitochondrial functional alterations might be rescued following pharmacological treatments, these results are of interest in the light of potential therapeutic interventions.