Epigallocatechin-3-gallate Prevents Oxidative Phosphorylation Deficit and Promotes Mitochondrial Biogenesis in Human Cells From Subjects With Down's Syndrome

Biochim Biophys Acta. 2013 Apr;1832(4):542-52. doi: 10.1016/j.bbadis.2012.12.011. Epub 2013 Jan 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cells, Cultured
  • Chromosomes, Human, Pair 21
  • Down Syndrome* / genetics
  • Down Syndrome* / physiopathology
  • Fibroblasts / drug effects
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mitochondria* / drug effects
  • Mitochondria* / genetics
  • Mitochondria* / pathology
  • Oxidative Phosphorylation / drug effects
  • Oxidative Stress / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Sirtuin 1 / metabolism
  • Tea / chemistry
  • Transcription Factors / metabolism
  • Trisomy

Substances

  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species
  • Tea
  • Transcription Factors
  • Adenosine Triphosphate
  • Catechin
  • epigallocatechin gallate
  • SIRT1 protein, human
  • Sirtuin 1