Regulation of the Mitochondrial BKCa Channel by the Citrus Flavonoid Naringenin as a Potential Means of Preventing Cell Damage

Abstract

<jats:p>Naringenin, a flavanone obtained from citrus fruits and present in many traditional Chinese herbal medicines, has been shown to have various beneficial effects on cells both in vitro and in vivo. Although the antioxidant activity of naringenin has long been believed to be crucial for its effects on cells, mitochondrial pathways (including mitochondrial ion channels) are emerging as potential targets for the specific pharmacological action of naringenin in cardioprotective strategies. In the present study, we describe interactions between the mitochondrial large-conductance calcium-regulated potassium channel (mitoBKCa channel) and naringenin. Using the patch-clamp method, we showed that 10 µM naringenin activated the mitoBKCa channel present in endothelial cells. In the presence of 30 µM Ca2+, the increase in the mitoBKCa channel probability of opening from approximately 0.25 to 0.50 at −40 mV was observed. In addition, regulation of the mitoBKCa channel by naringenin was dependent on the concentration of calcium ions. To confirm our data, physiological studies on the mitochondria were performed. An increase in oxygen consumption and a decrease in membrane potential was observed after naringenin treatment. In addition, contributions of the mitoBKCa channel to apoptosis and necrosis were investigated. Naringenin protected cells against damage induced by tumor necrosis factor α (TNF-α) in combination with cycloheximide. In this study, we demonstrated that the flavonoid naringenin can activate the mitoBKCa channel present in the inner mitochondrial membrane of endothelial cells. Our studies describing the regulation of the mitoBKCa channel by this natural, plant-derived substance may help to elucidate flavonoid-induced cytoprotective mechanisms.</jats:p>

Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

“…We have also demonstrated using patch clamp that naringenin directly activates the mitoBK Ca channel from endothelial mitochondria. Furthermore, naringenin prevents cell damage in this model [204]. Thus, mitochondrial ion channels are becoming promising new targets for flavonoids in cells.…”

“…Moreover, naringenin-induced activation of mitochondrial K + channels leads to mild mitochondrial uncoupling and results, as expected, in an increase in the mitochondrial respiration rate in these cells. In addition, our latest study indicates that in mitochondria isolated from human endothelial cells, naringenin stimulates inhibitor-sensitive mitoBK Ca channel-mediated K + flux, decreasing the mΔΨ and thus accelerating the mitochondrial oxygen consumption rate [ 204 ]. We have also demonstrated using patch clamp that naringenin directly activates the mitoBK Ca channel from endothelial mitochondria.…”

Naringenin, a Flavonoid, Modulates Gut Microbiome and Ameliorates Hormone Levels to Improve Polycystic Ovary Syndrome in Letrozole-induced Rats&nbsp;

“…All those features illustrated the model of PCOS were established. Interestingly, a avanone, naringenin extracted from citrus fruits and exist in many traditional Chinese herbal medicines, has been displayed to have multiple effective effects on cells both in vivo and in vitro [30]. The result of naringenin treatment was the estradiol level and ISI increased, the T, LH, FSH, FBG, FINS and HOMA-IR levels decreased when compared to the levels in PCOS group.…”

In Search of New Therapeutics—Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond

“…The conducted research has also shown that naringenin increasing the concentrations of enzymes removing reactive oxygen species and reducing oxidative stress is one of the characteristics of polycystic ovary syndrome. The cytoprotective and anti-inflammatory effects of naringenin were also described in [ 134 ], where the authors described the naringenin-mediated protection of cells against damage induced by TNF- in combination with cycloheximide in an in vitro experiment. The described properties of naringenin justify considering it as an element of PCOS therapy [ 133 ].…”