title: Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson's disease.
abstract: 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-1α (PGC-1α) 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-1α 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-1α 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-1α'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.
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferretta
authors.affiliation: Institute of Nanoscience-NNL, Consiglio Nazionale delle Ricerche (CNR), Lecce, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gaballo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Tanzarella
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Annese
authors.affiliation: Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, (CNR), Bari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Di Paola
authors.affiliation: Department of Neurology, 'Bonomo' Hospital, Andria (BA), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dell'aquila
authors.affiliation: Department of Neurology, 'Bonomo' Hospital, Andria (BA), Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: De Mari
authors.affiliation: Department of Neurology, 'Madonnina' Hospital, Bari, Italy.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Ferranini
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy. Electronic address: consiglia.pacelli@umontreal.ca.
authors.forename: Consiglia
authors.initials: C
authors.lastname: Pacelli
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Organs of Senses, University of Bari 'A. Moro', Bari, Italy. Electronic address: tizianamaria.cocco@uniba.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cocco
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013267:Stilbenes; D014157:Transcription Factors; D009243:NAD; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Mitochondria; PGC-1α; Parkin; Parkinson's disease; Resveratrol; Sirtuin 1