title: Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome.
abstract: A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) - a natural polyphenol component of green tea - to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1α deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content. In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy. d.valenti@biologia.uniba.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
authors.forename: Anna
authors.initials: A
authors.lastname: Signorile
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rossi
authors.forename: Lidia
authors.initials: L
authors.lastname: de Bari
authors.forename: Iris
authors.initials: I
authors.lastname: Scala
authors.forename: Barbara
authors.initials: B
authors.lastname: Granese
authors.forename: Sergio
authors.initials: S
authors.lastname: Papa
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Vacca
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D013662:Tea / Q000737:chemistry; D014157:Transcription Factors / Q000378:metabolism; D014314:Trisomy
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D013662:Tea; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D002392:Catechin; C045651:epigallocatechin gallate; C447939:SIRT1 protein, human; D056564:Sirtuin 1