Intracellular quercetin accumulation and its impact on mitochondrial dysfunction in intestinal Caco-2 cells

[Display omitted] •Quercetin metabolites accumulate in mitochondria of intestinal cells.•Mitochondrial stress induces an increased quercetin accumulation in intestinal cells.•Mitochondrial stress modulates quercetin intestinal metabolism.•Quercetin can partially restore mitochondrial function of intestinal cells. Flavonoid bioavailability and bioactivity is associated with interindividual variability, which is partially due to differences in health status. Previously, it was demonstrated that cellular stress, especially mitochondrial stress, increases intracellular quercetin uptake and this is associated with beneficial health effects. Here, the impact of quercetin on mitochondrial dysfunction, induced by stressors targeting different sites of the electron transport chain, is investigated. The influence of the mitochondrial stress on quercetin uptake and subcellular location is studied and the accumulated quercetin metabolites in intestinal Caco-2 cells and mitochondria are characterized. It was observed that quercetin counteracted (i) the carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP)-induced decrease in maximum oxygen consumption, (ii) the valinomycin-, oligomycin- and FCCP-induced reactive oxygen species production and (iii) the valinomycin-induced disruption of mitochondrial membrane potential. Using confocal microscopy, it was found that upon mitochondrial stress, the intracellular quercetin accumulation increased and was partially located in the mitochondria. Finally, it was demonstrated that quercetin was present as O-methyl, O-methylglucuronide and O-methylsulfate conjugates in the cell lysate and mitochondria-enriched fraction. This study shows that quercetin can partially restore, especially FCCP-induced, mitochondrial dysfunction and this protective effect was linked with an intracellular quercetin accumulation in the mitochondria of intestinal cells.