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
共 54 条
[1]   Gas sensing in microplates with optodes: Influence of oxygen exchange between sample, air, and plate material [J].
Arain, S ;
Weiss, S ;
Heinzle, E ;
John, GT ;
Krause, C ;
Klimant, I .
BIOTECHNOLOGY AND BIOENGINEERING, 2005, 90 (03) :271-280
[2]   In vivo and in organello assessment of OXPHOS activities [J].
Barrientos, A .
METHODS, 2002, 26 (04) :307-316
[3]   Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients' cells lacking its components [J].
Bastin, Jean ;
Aubey, Flore ;
Rotig, Agnes ;
Munnich, Arnold ;
Djouadi, Fatima .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (04) :1433-1441
[4]   Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts [J].
Bastin, Jean ;
Lopes-Costa, Alexandra ;
Djouadi, Fatima .
HUMAN MOLECULAR GENETICS, 2011, 20 (10) :2048-2057
[5]   Resveratrol improves health and survival of mice on a high-calorie diet [J].
Baur, Joseph A. ;
Pearson, Kevin J. ;
Price, Nathan L. ;
Jamieson, Hamish A. ;
Lerin, Carles ;
Kalra, Avash ;
Prabhu, Vinayakumar V. ;
Allard, Joanne S. ;
Lopez-Lluch, Guillermo ;
Lewis, Kaitlyn ;
Pistell, Paul J. ;
Poosala, Suresh ;
Becker, Kevin G. ;
Boss, Olivier ;
Gwinn, Dana ;
Wang, Mingyi ;
Ramaswamy, Sharan ;
Fishbein, Kenneth W. ;
Spencer, Richard G. ;
Lakatta, Edward G. ;
Le Couteur, David ;
Shaw, Reuben J. ;
Navas, Placido ;
Puigserver, Pere ;
Ingram, Donald K. ;
de Cabo, Rafael ;
Sinclair, David A. .
NATURE, 2006, 444 (7117) :337-342
[6]   Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome [J].
Bénit, P ;
Slama, A ;
Cartault, F ;
Giurgea, I ;
Chretien, D ;
Lebon, S ;
Marsac, C ;
Munnich, A ;
Rötig, A ;
Rustin, P .
JOURNAL OF MEDICAL GENETICS, 2004, 41 (01) :14-17
[7]   Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophlic cardiomyopathy and encephalopathy [J].
Bénit, P ;
Beugnot, R ;
Chretien, D ;
Giurgea, I ;
De Lonlay-Debeney, P ;
Issartel, JP ;
Corral-Debrinski, M ;
Kerscher, S ;
Rustin, P ;
Rötig, A ;
Munnich, A .
HUMAN MUTATION, 2003, 21 (06) :582-586
[8]   Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency [J].
Bénit, P ;
Chretien, D ;
Kadhom, N ;
de Lonlay-Debeney, P ;
Cormier-Daire, V ;
Cabral, A ;
Peudenier, S ;
Rustin, P ;
Munnich, A ;
Rötig, A .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (06) :1344-1352
[9]   Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein [J].
Bernier, Michel ;
Paul, Rajib K. ;
Martin-Montalvo, Alejandro ;
Scheibye-Knudsen, Morten ;
Song, Shaoming ;
He, Hua-Jun ;
Armour, Sean M. ;
Hubbard, Basil P. ;
Bohr, Vilhelm A. ;
Wang, Lili ;
Zong, Yaping ;
Sinclair, David A. ;
de Cabo, Rafael .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (22) :19270-19279
[10]   Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β [J].
Bowers, JL ;
Tyulmenkov, VV ;
Jernigan, SC ;
Klinge, CM .
ENDOCRINOLOGY, 2000, 141 (10) :3657-3667