Down syndrome (DS) is a common birth defect characterized by an extra copy of chromosome 21 that for approximately 95% of observed cases is caused by a meiotic non-disjunction event dur- ing gametogenesis. Individuals with trisomy 21 have typical phys- ical phenotypes besides mental retardation, early form of Alzheimer’s disease, pre-mature aging, congenital heart disease and immune hematologic anomalies. Several observations suggest that mitochondrial dysfunction may play an important role in the pathogenesis of DS[1]. In the present study, we have investigated some bioenergetic parameters of mitochondria from livers and brains of middle aged Ts65Dn mice, an animal model of DS with three copies of human chromosome 21 orthologs [2]. Our results indicate that the respiratory activities are decreased in the brain of Ts65Dn mice; in particular NADH oxidation in permeabilized mitochon- dria is reduced; flux control analysis of NADH oxidation shows that control by Complex I is slightly decreased indicating that some other step may have become more rate-controlling. Two- dimensional polyacrylamide gel electrophoresis (2D BN/SDS PAGE) suggests disruption of the supramolecular association of Complex III with Complex IV in the DS mice offering a possible explanation of the decrease of NADH oxidation accompanied by lower control by Complex I. A slight decrease of NADH-Coen- zyme Q reductase activity, however, suggests that Complex I is also partially affected. The most interesting result up to now has been the activation of the permeability transition observed in freshly isolated liver mitochondria of Ts65Dn mice. The results indicate that mtPTP responsiveness to stepwise calcium additions to mitochondria is dramatically increased in mitochondria of the mouse model Ts65Dn, evidencing an enhanced propensity to the permeability transition and thus to apoptotic cell death. References: 1. Coskun, PE et al. J Alzheimers Dis 2010; 20 s2: s293–310. 2. Moore CS, Roper RJ. Mamm Genome 2007; 18 : 431–443.
Faccioli M, Barbero G, Falasca AI, Genova ML, Lenaz G (2011). Mitochondrial dysfunction in Down syndrome.
Mitochondrial dysfunction in Down syndrome
FACCIOLI, MARCO;BARBERO, GIOVANNA;GENOVA, MARIA LUISA;LENAZ, GIORGIO
2011
Abstract
Down syndrome (DS) is a common birth defect characterized by an extra copy of chromosome 21 that for approximately 95% of observed cases is caused by a meiotic non-disjunction event dur- ing gametogenesis. Individuals with trisomy 21 have typical phys- ical phenotypes besides mental retardation, early form of Alzheimer’s disease, pre-mature aging, congenital heart disease and immune hematologic anomalies. Several observations suggest that mitochondrial dysfunction may play an important role in the pathogenesis of DS[1]. In the present study, we have investigated some bioenergetic parameters of mitochondria from livers and brains of middle aged Ts65Dn mice, an animal model of DS with three copies of human chromosome 21 orthologs [2]. Our results indicate that the respiratory activities are decreased in the brain of Ts65Dn mice; in particular NADH oxidation in permeabilized mitochon- dria is reduced; flux control analysis of NADH oxidation shows that control by Complex I is slightly decreased indicating that some other step may have become more rate-controlling. Two- dimensional polyacrylamide gel electrophoresis (2D BN/SDS PAGE) suggests disruption of the supramolecular association of Complex III with Complex IV in the DS mice offering a possible explanation of the decrease of NADH oxidation accompanied by lower control by Complex I. A slight decrease of NADH-Coen- zyme Q reductase activity, however, suggests that Complex I is also partially affected. The most interesting result up to now has been the activation of the permeability transition observed in freshly isolated liver mitochondria of Ts65Dn mice. The results indicate that mtPTP responsiveness to stepwise calcium additions to mitochondria is dramatically increased in mitochondria of the mouse model Ts65Dn, evidencing an enhanced propensity to the permeability transition and thus to apoptotic cell death. References: 1. Coskun, PE et al. J Alzheimers Dis 2010; 20 s2: s293–310. 2. Moore CS, Roper RJ. Mamm Genome 2007; 18 : 431–443.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
