Effect of resveratrol on mitochondrial function: Implications in parkin-associated familiar Parkinson's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Ferretta, Anna¹  Gaballo, Antonio²  Tanzarella, Paola¹  Piccoli, Claudia³  Capitanio, Nazzareno³  Nico, Beatrice¹  Annese, Tiziana¹  Di Paola, Marco⁴  Dell'Aquila, Claudia⁵  De Mari, Michele⁵  Ferranini, Ermanno⁶  Bonifati, Vincenzo⁷  Pacelli, Consiglia¹  Cocco, Tiziana¹ 

[1] Univ Bari A Moro, Dept Basic Med Sci Neurosci & Organs Senses, I-70124 Bari, Italy

[2] CNR, Inst Nanosci NNL, Lecce, Italy

[3] Univ Foggia, Dept Clin & Expt Med, Foggia, Italy

[4] CNR, Inst Biomembranes & Bioenerget, I-70126 Bari, Italy

[5] Bonomo Hosp, Dept Neurol, Andria, BA, Italy

[6] Madonnina Hosp, Dept Neurol, Bari, Italy

[7] Erasmus MG, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands

关键词: Parkinson's disease;    Parkin;    Mitochondria;    Resveratrol;    PGC-1 alpha;    Sirtuin 1;   

DOI  :  10.1016/j.bbadis.2014.02.010

来源: Elsevier

【 摘 要 】

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but the molecular mechanisms controlling these events are not completely understood. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a transcriptional coactivator known as master regulator of mitochondrial functions and oxidative metabolism. Recent studies, including one from our group, have highlighted altered PGC-1 alpha activity and transcriptional deregulation of its target genes in PD pathogenesis suggesting it as a new potential therapeutic target. Resveratrol, a natural polyphenolic compound proved to improve mitochondrial activity through the activation of several metabolic sensors resulting in PGC-1 alpha activation. Here we have tested in vitro the effect of resveratrol treatment on primary fibroblast cultures from two patients with early-onset PD linked to different Park2 mutations. We show that resveratrol regulates energy homeostasis through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and raise of mRNA expression of a number of PGC-1 alpha's target genes resulting in enhanced mitochondrial oxidative function, likely related to a decrease of oxidative stress and to an increase of mitochondrial biogenesis. The functional impact of resveratrol treatment encompassed an increase of complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial ATP production and a decrease in lactate content, thus supporting a switch from glycolytic to oxidative metabolism. Moreover, resveratrol treatment caused an enhanced macro-autophagic flux through activation of an LC3-independent pathway. Our results, obtained in early-onset PD fibroblasts, suggest that resveratrol may have potential clinical application in selected cases of PD-affected patients. (C) 2014 Elsevier B.V. All rights reserved.

【 授权许可】

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