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.

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

“…Mitochondria are critical for ATP production, and many small molecules that activate AMPK, including metformin, resveratrol, berberine, and rotenone, have been shown to inhibit mitochondrial function (50)(51)(52)(53)(54). To produce ATP, ADP must enter the mitochondria through VDAC in the outer membrane and the adenine nucleotide transporter (ANT) in the inner membrane, be converted to ATP through oxidative phosphorylation, and then exit the mitochondria again through ANT and VDAC.…”

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

“…Our laboratory and that of others have demonstrated that the natural antioxidant resveratrol improves organ function following severe hemorrhage (23)(24)(25). Resveratrol has been shown to enhance mitochondrial function as well as biogenesis, and has been implicated in the extension of life span in several species (26)(27)(28)(29). However, determining the effect of resveratrol in reducing mortality or prolonging survival following hemorrhagic shock is important toward initiating clinical trials to use this agent as an adjunct to resuscitation fluid following severe hemorrhage.…”

Resveratrol: A miraculous natural compound for diseases treatment

“…Several lines of evidence showed the improvement of mitochondrial respiratory capacities by RSV treatment. In fact, RSV activates SIRT1‐AMPK pathway and then induces PGC‐1alpha activity (Ferretta et al., 2014). PGC‐1alpha activation leads to mitochondrial biogenesis and amelioration of its function.…”