Mitochondrial translocation of vitamin D receptor is mediated by the permeability transition pore in human keratinocyte cell line

PLoS One. 2013;8(1):e54716. doi: 10.1371/journal.pone.0054716. Epub 2013 Jan 22.

Abstract

Background: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Ligands
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins* / metabolism
  • Mitochondrial Membrane Transport Proteins* / physiology
  • Mitochondrial Permeability Transition Pore
  • Protein Transport*
  • Receptors, Calcitriol / metabolism*
  • Receptors, Calcitriol / physiology
  • Retinoid X Receptors / metabolism

Substances

  • Ligands
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Receptors, Calcitriol
  • Retinoid X Receptors

Grant support

This work was supported by Ministero dell’Istruzione Università e Ricerca. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.