Abstract

A central role for mitochondrial dysfunctions has been proposed in the pathogenesis of Down syndrome (DS), a multifactorial disorder caused by trisomy of human chromosome 21. To explore whether and how abnormalities in mitochondrial energy metabolism are involved in DS pathogenesis, we investigated the catalytic properties, gene expression and protein levels of certain proteins involved in mitochondrial ATP synthesis such as ATPase, ADP/ATP translocator (ANT) and adenylate kinase (AK) in human skin fibroblasts from subjects with DS (DS-HSF) comparing them with euploid fibroblasts. In DS-HSF, we found a strong impairment of mitochondrial ATP synthesis due to a reduction in the catalytic efficiency of each of the investigated proteins. This impairment occurred in spite of unchanged gene expression and an increase in ANT and AK protein content, whereas the amount of ATPase subunits was selectively reduced. Interestingly, exposure of DS-HSF to dibutyryl-cAMP, a permanent derivative of cAMP, stimulated ANT, AK and ATPase activities whereas H89, a specific PKA inhibitor, suppressed this cAMP-dependent activation, indicating an involvement of cAMP/PKA-mediated signalling pathway in ATPase, ANT and AK deficit. Consistently, DS-HSF showed decreased basal levels of cAMP and reduced PKA activity.Despite the impairment of mitochondrial energy apparatus, no changes in cellular energy status but increased basal levels of L-lactate were found in DS-HSF which partially offset for mitochondrial energy deficit by increasing glycolysis and mitochondrial mass.These results give new insight into the molecular basis for mitochondrial dysfunction in DS and might provide a molecular explanation for some clinical features of the syndrome.

Autore Pugliese

• Tullo Apollonia , Valenti Daniela , Merafina Riccardo Sandro , Vacca Rosa Anna

Tutti gli autori

• Valenti D.; Tullo A.; Caratozzolo M.F.; Merafina R.S.; Scartezzini P.; Marra E.; Vacca R.A.

Titolo volume/Rivista

Biochemical journal

Anno di pubblicazione

2010

ISSN

0264-6021

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile