Mitochondrial Translocation of Vitamin D Receptor Is Mediated by the Permeability Transition Pore in Human Keratinocyte Cell Line

Abstract

BackgroundVitamin D receptor (VDR) is a well known transcriptional regulator, active as heterodimer in association with coactivators and corepressors. In addition it has been described the extranuclear distribution of the receptor and in particular the recently reported mitochondrial localization in platelets and megakaryocytes is intriguing because it appears to be a common feature of steroid receptors. Whereas for other members of the steroid receptor family the mitochondrial function has been explored, up to now nothing is known about a mitochondrial form of VDR in human proliferating cells.Methodology/Principal FindingsIn this study we characterized for the first time the mitochondrial localization of VDR in the human keratinocyte cell line HaCaT. In proliferating HaCaT cells VDR was abundantly expressed in mitochondria in association with its binding partner RXRα and the import was ligand-independent. By immunoprecipitation studies we demonstrated the interaction of VDR with proteins of the permeability transition pore (PTP), VDAC and StAR. We then adopted different pharmacological and silencing approaches with the aim of hampering PTP function, either affecting PTP opening or abating the expression of the complex member StAR. By all means the impairment of pore function led to a reduction of mitochondrial levels of VDR.ConclusionsThe results reported here demonstrate a ligand-independent mitochondrial import of VDR through the permeability transition pore, and open interesting new perspectives on PTP function as transporter and on VDR role in mitochondria.

Vitamin D receptor-modulated Hsp70/AT1 expression may protect the kidneys of SHRs at the structural and functional levels

“…This finding is feasible taking into consideration recent contributions that reported the identification and characterization of a functional mitochondrial RAS (Abadir et al 2011), the mitochondrial localization of VDR (García et al 2012 andSilvagno et al 2010), and ultrastructural mitochondrial improvement as a consequence of recovery in mitochondrial VDR expression linked to poor AT 1 and NADPH oxidase activity during obstructive nephropathy. Moreover, a ligand-independent mitochondrial import of VDR through the permeability transition pore (PTP) was reported (Silvagno et al 2013); and since functional and structural changes in mitochondria are caused by the opening of the mitochondrial PTP and by the mitochondrial generation of ROS, this finding open new perspectives on PTP function as transporter and on VDR role in mitochondria.…”

Molecular actions of vitamin D in reproductive cell biology

“…These interactions may have important implications for the rapid non-genomic responses observed previously, like the insulinotropic actions in pancreatic β-cells (Kajikawa et al 1999) and are unlike those observed for nuclear or membrane VDR. In addition, mito-VDR is dependent on mitochondrial permeability proteins, where inhibition of these significantly reduced VDR accumulation and resulted in altered cell proliferation, enhanced mitochondrial membrane potential along with increased mitochondrial respiration (Silvagno et al 2013, Consiglio et al 2014. The biological function of mito-VDR is believed to involve modulation of electron transport chain (ETC) activity and lipid metabolism (Consiglio et al 2014), and the VDR receptor may directly regulate respiratory protein expression coded by mitochondrial DNA.…”

Mitochondrial Hormone Receptors - an Emerging Field of Signaling in the Cell’s Powerhouse

“…The p43 protein was shown to stimulate mitochondrial gene expression and to influence cell differentiation and apoptosis [16], whereas the role of p28 remains to be identified. The vitamin D 3 receptor (VDR) was also detected in mitochondria [17][18][19][20][21]. VDR translocation was reported to take place via the permeability transition pore [18].…”

“…The vitamin D 3 receptor (VDR) was also detected in mitochondria [17][18][19][20][21]. VDR translocation was reported to take place via the permeability transition pore [18]. VDR signaling seems to mainly result in the suppression of respiratory activity [19][20][21].…”