Resveratrol Inhibition of Cellular Respiration: New Paradigm for an Old Mechanism

Abstract

Resveratrol (3,4′,5-trihydroxy-trans-stilbene, RSV) has emerged as an important molecule in the biomedical area. This is due to its antioxidant and health benefits exerted in mammals. Nonetheless, early studies have also demonstrated its toxic properties toward plant-pathogenic fungi of this phytochemical. Both effects appear to be opposed and caused by different molecular mechanisms. However, the inhibition of cellular respiration is a hypothesis that might explain both toxic and beneficial properties of resveratrol, since this phytochemical: (1) decreases the production of energy of plant-pathogenic organisms, which prevents their proliferation; (2) increases adenosine monophosphate/adenosine diphosphate (AMP/ADP) ratio that can lead to AMP protein kinase (AMPK) activation, which is related to its health effects, and (3) increases the reactive oxygen species generation by the inhibition of electron transport. This pro-oxidant effect induces expression of antioxidant enzymes as a mechanism to counteract oxidative stress. In this review, evidence is discussed that supports the hypothesis that cellular respiration is the main target of resveratrol.

Dosis Facit Sanitatem—Concentration-Dependent Effects of Resveratrol on Mitochondria

“…This huge, diverse group of plant metabolites includes well-known compounds, such as the phytoalexin, resveratrol (3,4′,5-trihydroxy- trans -stilbene; RSV) and the flavonoid, quercetin [ 2 ]. The actions of RSV have been studied in several in vivo and in vitro approaches, demonstrating antioxidant, anti-inflammatory and anti-aging effects [ 3 ], but also pro-apoptotic anti-cancer properties [ 4 , 5 ] as well as antimicrobial activity [ 6 ].…”

“…Since RSV is produced by plants to fight against microbes [ 1 ], it seems reasonable that this specific compound also strongly affects mitochondria, which are thought to be descendants from ancient bacteria that have been incorporated as an endosymbiont into an ancestor in the modern eukaryotic cell [ 2 , 3 ]. By hosting the complexes of the respiration chain in their inner membranes (IMM), mitochondria are the predominant source for the cell’s most important energy carrier, adenosine triphosphate (ATP).…”

Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase

“…The demand for evidence-based phytochemicals in general and plant-based phenolic constituents in particular as alternative remedies has increased [7, 13, 16–20]. A large number of dietary phenolic compounds from a variety of sources have been shown to have potential antitumor or antimicrobial properties [21–25].…”

Functional Mitochondria Are Important for the Effect of Resveratrol

“…On the other hand, experiments with isolated mitochondria show that Resv decreased the activity of several complexes in the electron transport chain (ETC) [ 10 , 11 ] and directly interacted with complex I [ 12 ]. Therefore, inhibition of the cellular respiration is suggested to be one of the primary targets of the cytotoxic effects of resveratrol [ 13 ].…”