Resveratrol induces mitochondrial dysfunction and decreases chronological life span of Saccharomyces cerevisiae in a glucose-dependent manner

Abstract

A broad range of health benefits have been attributed to resveratrol (RSV) supplementation in mammalian systems, including the increases in longevity. Nonetheless, despite the growing number of studies performed with RSV, the molecular mechanism by which it acts still remains unknown. Recently, it has been proposed that inhibition of the oxidative phosphorylation activity is the principal mechanism of RSV action. This mechanism suggests that RSV might induce mitochondrial dysfunction resulting in oxidative damage to cells with a concomitant decrease of cell viability and cellular life span. To prove this hypothesis, the chronological life span (CLS) of Saccharomyces cerevisiae was studied as it is accepted as an important model of oxidative damage and aging. In addition, oxygen consumption, mitochondrial membrane potential, and hydrogen peroxide (HO) release were measured in order to determine the extent of mitochondrial dysfunction. The results demonstrated that the supplementation of S. cerevisiae cultures with 100 μM RSV decreased CLS in a glucose-dependent manner. At high-level glucose, RSV supplementation increased oxygen consumption during the exponential phase yeast cultures, but inhibited it in chronologically aged yeast cultures. However, at low-level glucose, oxygen consumption was inhibited in yeast cultures in the exponential phase as well as in chronologically aged cultures. Furthermore, RSV supplementation promoted the polarization of the mitochondrial membrane in both cultures. Finally, RSV decreased the release of HO with high-level glucose and increased it at low-level glucose. Altogether, this data supports the hypothesis that RSV supplementation decreases CLS as a result of mitochondrial dysfunction and this phenotype occurs in a glucose-dependent manner.

Resveratrol cytotoxicity is energy‐dependent

“…Yeast cultures grown at a high glucose level (10% of glucose) exhibited an increase in basal respiration and maximal respiratory capacity as the resveratrol concentration increased. At a standard glucose level (2% of glucose), resveratrol affects the respiratory capacity only at 100 μM, while at a low glucose level (0.5% of glucose), resveratrol supplementation inhibited the respiratory capacity of S. cerevisiae at all concentrations tested, supporting the hypothesis that the primary target of resveratrol is the inhibition of cellular respiration (Ramos‐Gomez et al, ).…”

“…Thus, resveratrol at low doses acts as a pro‐oxidative molecule causing mild oxidative stress and consequently promotes the activation of the antioxidant systems as a cellular defense (Plauth et al, ). In this regard, resveratrol supplementation at 10, 30, 50, and 100 μM into S. cerevisiae cultures grown in 10% of glucose diminished H 2 O 2 release, while in 2% of glucose, H 2 O 2 release was diminished only at 100 μM, and in 0.5% of glucose, resveratrol (10 μM) promoted a higher release of H 2 O 2 (Ramos‐Gomez et al, ). Therefore, resveratrol may have an antioxidant effect at the physiological level or a pro‐oxidant cytotoxic effect, depending on the concentrations of resveratrol and the energy state of the cell, suggesting that by modifying the energetic state of the cell, it is possible to increase the cytotoxic effect of resveratrol.…”

“…Resveratrol cytotoxic effects have been reported in S. cerevisiae (Ramos‐Gomez et al, ), human lung adenocarcinoma ASTC‐a‐1 cells (Zhang, Wang, & Chen, ), human pancreatic Bx‐PC‐3 cancer cells (Ma et al, ), and rat B103 neuroblastoma cells (Rahman, Kim, Kim, Oh, & Huh, ). In addition, mitochondriotropic resveratrol derivatives showed strong cytotoxic effects in mouse colon cancer CT‐26 cells (Sassi, Mattarei, Azzolini, Bernardi, et al, ; Sassi, Mattarei, Azzolini, Szabo, et al, ), suggesting that the cytotoxic mechanism of resveratrol should be universal for several eukaryotic cells.…”

“…Moreover, it has been proven that the beneficial effects of resveratrol supplementation are glucose‐dependent and that the cell viability of S. cerevisiae was reduced at low glucose concentrations (0.1% and 0.5% of glucose) vs. the cell viability of cells at high glucose concentrations (10% of glucose) when cultures were supplemented with 1,000 μM of resveratrol (Madrigal‐Perez et al, ). Furthermore, a reduction in the chronological lifespan of S. cerevisiae was observed when the same concentration (100 μM) of resveratrol was supplemented in yeast cultures grown with 2 and 0.5% of glucose (Ramos‐Gomez et al, ). In addition, as the resveratrol concentration increased and the carbon concentration diminished, the cytotoxic effect of resveratrol was more evident (Madrigal‐Perez et al, ; Ramos‐Gomez et al, ).…”

“…Furthermore, a reduction in the chronological lifespan of S. cerevisiae was observed when the same concentration (100 μM) of resveratrol was supplemented in yeast cultures grown with 2 and 0.5% of glucose (Ramos‐Gomez et al, ). In addition, as the resveratrol concentration increased and the carbon concentration diminished, the cytotoxic effect of resveratrol was more evident (Madrigal‐Perez et al, ; Ramos‐Gomez et al, ). Thus, it appears that resveratrol mimics the beneficial effects of caloric restriction on lifespan only when cells are at high glucose concentrations and in specific resveratrol concentrations, while at low glucose concentrations, resveratrol is highly cytotoxic.…”