Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Valenti, Daniela¹  De Rasmo, Domenico¹  Signorile, Anna²  Rossi, Leonardo³  de Bari, Lidia¹  Scala, Iris⁴  Granese, Barbara⁴  Papa, Sergio¹  Vacca, Rosa Anna¹ 

[1] CNR, Inst Biomembranes & Bioenerget, I-70126 Bari, Italy

[2] CNR, Dept Basic Med Sci Neurosci & Sense Organs, I-70126 Bari, Italy

[3] Univ Pisa, Dept Clin & Expt Med, Lab Biol & Genet, I-56100 Pisa, Italy

[4] Univ Naples Federico II, Dept Pediat, Naples, Italy

关键词: Down syndrome;    EGCG;    Mitochondria;    Sirt1;    PGC-1 alpha;    cAMP/PKA pathway;   

DOI  :  10.1016/j.bbadis.2012.12.011

来源: Elsevier

【 摘 要 】

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-1 alpha 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. (C) 2012 Elsevier B.V. All rights reserved.

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