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

Anna Kicinska,Wieslawa Jarmuszkiewicz,Jan Daniluk,Rafał P Kampa,Piotr Bednarczyk,Adam Szewczyk,Aleksandra Sek

doi:10.3390/molecules25133010

Abstract

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.

Highlights

Naringenin, a metabolite of naringin, belongs to a large group of polyphenolic compounds that are widely distributed in all food products of plant origin
The current study addresses the effects of the citrus flavonoid naringenin on the mitoBKCa channel present in the mitochondria of endothelial cells
After adding the mitochondrial suspension to hypotonic medium, mitochondrial swelling begins due to osmotic shock, which causes a rupture of the outer membrane and the formation of vesicles deprived of the outer membrane, i.e., mitoplasts

Summary

Introduction

Naringenin, a metabolite of naringin, belongs to a large group of polyphenolic compounds that are widely distributed in all food products of plant origin. Naringenin has been shown to have various beneficial effects on cells both in vitro and in vivo, e.g., antiviral, anticancer, antidiabetic, anti-inflammatory and cardioprotective properties [2]. The antioxidant activity of naringenin has long been thought to be a crucial factor in its cellular effects, mitochondrial pathways (including mitochondrial ion channels) are currently emerging as potential targets for the specific pharmacological action of naringenin in anti-ischemic, cardioprotective strategies [3,4,5]. A variety of different potassium channels, including large-, intermediate- and small-conductance (BKCa , IKCa and SKCa ) channels, are expressed in the plasma membrane of vascular wall cells [7]. Some studies suggest that BKCa channels are preferentially expressed in the vascular smooth muscle cell plasma membrane, while IKCa and SKCa are usually located in the endothelial cell plasma membrane [8]

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