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

Mar 4, 2014Biochimica et biophysica acta

Resveratrol's impact on energy production in cells linked to inherited Parkinson's disease caused by parkin

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Abstract

Resveratrol treatment in primary fibroblast cultures from two patients with early-onset Parkinson's disease improved mitochondrial function and energy metabolism.

Resveratrol activated AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), influencing energy homeostasis.
mRNA expression of several PGC-1α target genes increased, indicating enhanced mitochondrial oxidative function.
Treatment led to increased activities of complex I and citrate synthase, as well as increased basal oxygen consumption and mitochondrial ATP production.
A decrease in lactate content suggests a metabolic shift from glycolysis to oxidative metabolism.
Resveratrol also enhanced macro-autophagic flux through activation of an LC3-independent pathway.

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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.

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

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