title: Impairment of F1F0-ATPase, adenine nucleotide translocator and adenylate kinase causes mitochondrial energy deficit in human skin fibroblasts with chromosome 21 trisomy.
abstract: A central role for mitochondrial dysfunction has been proposed in the pathogenesis of DS (Down's syndrome), 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 F1F0-ATPase, ANT (adenine nucleotide translocator) and AK (adenylate kinase), in DS-HSF (human skin fibroblasts with trisomic karyotype), 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 (protein kinase A) inhibitor, suppressed this cAMPdependent activation, indicating an involvement of the cAMP/PKA-mediated signalling pathway in the 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 the mitochondrial energy deficit by increasing glycolysis and mitochondrial mass.These results provide new insight into the molecular basis for mitochondrial dysfunction in DS and might provide a molecular explanation for some clinical features of the syndrome.
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari, Italy. d.valenti@biologia.uniba.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.forename: Apollonia
authors.initials: A
authors.lastname: Tullo
authors.forename: Mariano F
authors.initials: MF
authors.lastname: Caratozzolo
authors.forename: Riccardo S
authors.initials: RS
authors.lastname: Merafina
authors.forename: Paolo
authors.initials: P
authors.lastname: Scartezzini
authors.forename: Ersilia
authors.initials: E
authors.lastname: Marra
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Vacca
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D014314:Trisomy / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase; D006180:Proton-Translocating ATPases