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.

Mitochondrial Quality Control as a Therapeutic Target

“…For instance, isoflavones (genistein, daidzein, and formononetin) in rabbit renal proximal tubular cells (Rasbach and Schnellmann, 2008), flavones (baicalein, its 7-O-glucuronide baicalin, and wogonin) in L6 skeletal muscle cells (Im et al, 2012), and flavan-3-ol epigallocatechin-3-gallate in skin fibroblasts from Down's syndrome patients (Valenti et al, 2013) all activate the SIRT1/ PGC-1a pathway. In contrast to the SIRT1-inducing effect of genistein (Rasbach and Schnellmann, 2008), this isoflavone also reduces SIRT1 mRNA and protein expression and induces SIRT1 nuclear exclusion into the cytosol of the human prostate cancer cell lines LNCaP and PC-3 (Kikuno et al, 2008).…”

Molecular mechanism of epigallocatechin-3-gallate in human esophageal squamous cell carcinoma in vitro and in vivo

“…Although EGCG shows a cytoprotective effect at low concentrations (10-20 µM) (37), it has been reported that consumption of green tea-derived supplements at a high dose (120 mg/kg) can produce toxic effects in rodents (38).…”

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

“…Mitochondrial function is notably impaired in DS, 21 which may contribute to several DS-linked developmental abnormalities. In lymphoblast and fibroblast cultures from DS subjects treatment with EGCG (20 mM) has been shown to rescue mitochondrial function and promote mitochondrial biogenesis.…”

“…In lymphoblast and fibroblast cultures from DS subjects treatment with EGCG (20 mM) has been shown to rescue mitochondrial function and promote mitochondrial biogenesis. 21 This study prompted research aimed at establishing whether a similar effect was replicated in vivo. 22 A child (10-year and 3-monh-old) with DS was treated with ECCG (10 mg/kg/day) plus fish oil daily for six months.…”