Department of Oncology, University of Torino, Torino, Italy.
PLoS One. 2013;8(1):e54716. doi: 10.1371/journal.pone.0054716. Epub 2013 Jan 22.
Vitamin 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 FINDINGS: In 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.
The 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.
维生素 D 受体（VDR）是一种众所周知的转录调节因子，作为与共激活因子和核心抑制剂结合的异二聚体发挥作用。此外，已经描述了受体的核外分布，特别是最近报道的血小板和巨核细胞中的线粒体定位，这很有趣，因为它似乎是甾体受体的共同特征。虽然其他甾体受体家族成员的线粒体功能已经被探索过，但到目前为止，关于人类增殖细胞中 VDR 的线粒体形式还一无所知。
方法/主要发现：在这项研究中，我们首次描述了 VDR 在人角质形成细胞系 HaCaT 中的线粒体定位。在增殖的 HaCaT 细胞中，VDR 与结合伴侣 RXRα大量表达在线粒体中，且这种表达与配体无关。通过免疫沉淀研究，我们证明了 VDR 与通透性转换孔（PTP）、VDAC 和 StAR 蛋白的相互作用。然后，我们采用了不同的药理学和沉默方法来干扰 PTP 的功能，无论是影响 PTP 的开放还是减弱复合物成员 StAR 的表达。所有这些方法都导致了线粒体 VDR 水平的降低。
这里报道的结果表明，VDR 通过通透性转换孔进行配体非依赖性的线粒体导入，并为 PTP 作为转运蛋白的功能以及 VDR 在线粒体中的作用开辟了新的有趣视角。
