Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1832, Issue 4, Pages 542-552Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2012.12.011
Keywords
Down syndrome; EGCG; Mitochondria; Sirt1; PGC-1 alpha; cAMP/PKA pathway
Funding
- Italian Ministry of Instruction, University and Research (MIUR) - PRIN [2008FHM37R_002]
- MIUR - Programma FIRB-MERIT [1-RBNE0 8HWLZ-012]
- MIUR - Progetto FIRS Futuro in Ricerca [RBFR0813Z5]
- Fondation Jerome Lejeune (Oxidative stress and mitochondrial dysfunctions in Down syndrome)
- Galliera Genetic Bank - Network of Telethon Genetic Biobanks [GTB07001]
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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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