Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts

Abstract

Flavonoids belong to a large group of polyphenolic compounds that are widely present in plants. Certain flavonoids, including naringenin, have cytoprotective properties. Although the antioxidant effect has long been thought to be a crucial factor accounting for the cellular effects of flavonoids, mitochondrial channels have emerged recently as targets for cytoprotective strategies. In the present study, we characterized interactions between naringenin and the mitochondrial potassium (mitoBKCa and mitoKATP) channels recently described in dermal fibroblasts. With the use of the patch‐clamp technique and mitoplasts isolated from primary human dermal fibroblast cells, our study shows that naringenin in micromolar concentrations leads to an increase in mitoBKCa channel activity. The opening probability of the channel decreased from 0.97 in the control conditions (200 μmol/L Ca2+) to 0.06 at a low Ca2+ level (1 μmol/L) and increased to 0.85 after the application of 10 μmol/L naringenin. Additionally, the activity of the mitoKATP channel increased following the application of 10 μmol/L naringenin. To investigate the effects of naringenin on mitochondrial function, the oxygen consumption of dermal fibroblast cells was measured in potassium‐containing media. The addition of naringenin significantly and dose‐dependently increased the respiratory rate from 5.8 ± 0.2 to 14.0 ± 0.6 nmol O2 × min−1 × mg protein−1. Additionally, a Raman spectroscopy analysis of skin penetration indicated that the naringenin was distributed in all skin layers, including the epidermis and dermis. In this study, we demonstrated that a flavonoid, naringenin, can activate two potassium channels present in the inner mitochondrial membrane of dermal fibroblasts.

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

“…In our experimental model, we also examine in detail the functional role of the mitoBK Ca channel. The presented study complements the previous biochemical and functional characteristics of the mitoBK Ca channels present in fibroblast cells [30] and in vascular smooth muscle cells [31].…”

“…In our previous study, we observed a similar interaction of naringenin with the mitoBK Ca channel identified in the mitochondria of human skin fibroblasts [30]. However, the stimulatory effects of naringenin on the mitoBK Ca channel in skin fibroblasts were stronger than those observed in endothelial cells.…”

Mitochondrial Potassium Channels as Druggable Targets

“…Recently, the cardioprotective function of naringenin due to activation of the cardiac mitoBK Ca channel was shown [114]. Additionally, with the use of patch-clamp single channel measurements, it was shown in skin fibroblasts that both the mitoK ATP and mitoBK Ca channels were activated by naringenin [111]. These studies suggest that naringenin may function as a potassium channel opener towards mitochondrial potassium channels in skin-derived cells.…”

“…Drug repositioning involves the investigation of existing drugs for new therapeutic applications. Recently, a new set of mitochondrial potassium channels was discovered in skin-derived cells: keratinocytes, dermal fibroblasts, and endothelial cells [25,35,40,53,111]. Naringenin, a plant-derived flavonoid, has been known for many years to have the potential to improve many health problems, such as cardiovascular, metabolic, neurological, and pulmonary disorders; and cancer [112,113].…”

Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

“…The naringenin-induced effects observed in this study were again antagonized by paxilline. In 2019, Kampa et al finally showed the direct interaction of the flavonoid naringenin with mitochondrial potassium channels [203]. It has been demonstrated using isolated mitoplasts from primary human dermal fibroblasts and patch-clamp that naringenin at micromolar concentrations directly increases mitoBK Ca and mitoK ATP channel activity.…”