共 54 条
Beneficial effects of resveratrol on respiratory chain defects in patients fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling
被引:52
作者:
Costa, Alexandra Lopes
[1
]
Le Bachelier, Carole
[1
]
Mathieu, Lise
[1
]
Rotig, Agnes
[2
,3
]
Boneh, Avihu
[4
,5
]
De Lonlay, Pascale
[2
,3
,6
]
Tarnopolsky, Mark A.
[7
]
Thorburn, David R.
[4
,5
]
Bastin, Jean
[1
,8
]
Djouadi, Fatima
[1
,8
]
机构:
[1] Univ Paris 05, INSERM U747, F-75270 Paris 06, France
[2] Univ Paris 05, Inst Imagine, Sorbonne Paris Cite, F-75270 Paris 06, France
[3] Univ Paris 05, INSERM U781, Sorbonne Paris Cite, F-75270 Paris 06, France
[4] Univ Melbourne, Dept Paediat, Murdoch Childrens Res Inst, Melbourne, Vic, Australia
[5] Univ Melbourne, Royal Childrens Hosp, Melbourne, Vic, Australia
[6] Hop Necker Enfants Malad, Ctr Reference Malad Metab, Paris, France
[7] McMaster Univ, Neuromuscular & Neurometab Unit, Hamilton, ON, Canada
[8] Assistance Publ Hop Paris, Paris, France
关键词:
FATTY-ACID OXIDATION;
GENE-EXPRESSION;
ERR-ALPHA;
IN-VIVO;
MITOCHONDRIAL;
SIRT1;
MUTATIONS;
ACTIVATION;
PGC-1-ALPHA;
METABOLISM;
D O I:
10.1093/hmg/ddt603
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients fibroblasts. We show that RSV stimulates the expression of a panel of proteins representing structural subunits or assembly factors of the five RC complexes, in control fibroblasts. In moderate RC-deficient patients cells, RSV treatment increases the amount of mutated proteins and stimulates residual enzyme activities. In these patients cells, we establish that up-regulation of RC enzyme activities induced by RSV translates into increased cellular O-2 consumption rates and results in the correction of RC deficiencies. Importantly, RSV also prevents the accumulation of lactate that occurred in RC-deficient fibroblasts. Different complementary approaches demonstrate that RSV induces a mitochondrial biogenesis that might underlie the increase in mitochondrial capacities. Finally, we showed that, in human fibroblasts, RSV stimulated mitochondrial functions mainly in a SIRT1- and AMPK-independent manner and that its effects rather involved the estrogen receptor (ER) and estrogen-related receptor alpha (ERR) signaling pathways. These results represent the first demonstration that RSV could have a beneficial effect on inborn CI and CIV deficiencies from nuclear origin, in human fibroblasts and might be clinically relevant for the treatment of some RC deficiencies.
引用
收藏
页码:2106 / 2119
页数:14
相关论文