Mitochondrial Localization of Vitamin D Receptor in Human Platelets and Differentiated Megakaryocytes

Abstract

BackgroundLike other steroid hormones, vitamin D elicits both transcriptional events and rapid non genomic effects. Vitamin D receptor (VDR) localization and mechanisms of VDR-triggered non genomic responses are still controversial. Although anticoagulant effects of vitamin D have been reported and VDR signalling has been characterized in monocytes and vascular cells, nothing is known about VDR expression and functions in human platelets, anucleated fragments of megakaryocytes which are known targets of other steroids.Methodology/Principal FindingsIn this study we characterized the expression and cellular localization of VDR in human platelets and in a megakaryocyte lineage. Human platelets and their TPA-differentiated precursors expressed a classical 50 kDa VDR protein, which increased with megakaryocytes maturation. By biochemical fractionation studies we demonstrated the presence of the receptor in the soluble and mitochondrial compartment of human platelets, and the observation was confirmed by immunoelectron microscopy analysis. Similar localization was found in mature megakaryocytes, where besides its classical nuclear localization the receptor was evident as soluble and mitochondria resident protein.ConclusionsThe results reported here suggest that megakaryocytopoiesis and platelet activation, which are calcium-dependent events, might be modulated by a mitochondrial non genomic activity of VDR. These data open challenging future studies on VDR physiological role in platelets and more generally in mitochondria.

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

“…In this context, we show that mitochondrial injury linked to AT 1 /VDR uncoupling was improved when paricalcitol, enalapril, or, better still, the combination of both was used. 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.…”

Vitamin D and Cardiovascular Disease

“…20 VDRs have been found in all the major cardiovascular cell types, including VSMC, 21 EC, 22 cardiomyocytes, 23 most immune cells, 24 and platelets. 25 VDR binds 1,25(OH) 2 D with high affinity and specificity and then heterodimerizes predominantly with retinoid X receptor ( Figure 2). Structurally, VDR consists of a short N-terminal domain before the DNA-binding domain comprising 2 zinc fingers, the first conferring vitamin D response element specificity and the second providing a site for heterodimerization.…”

Molecular actions of vitamin D in reproductive cell biology

“…Some of the most interesting advances in VitD signalling are the recent studies demonstrating VDR translocation to the mitochondria (mito-VDR) in various cell types and the subsequent direct impact on cell metabolism (Silvagno et al 2010, Consiglio et al 2014. 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.…”