A truncated progesterone receptor (PR-M) localizes to the mitochondrion and controls cellular respiration

Mol Endocrinol. 2013 May;27(5):741-53. doi: 10.1210/me.2012-1292. Epub 2013 Mar 21.


The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-binding domains. In this report, we have localized PR-M to mitochondria using immunofluorescent localization of a PR-M-green fluorescent protein (GFP) fusion protein and in Western blot analyses of purified human heart mitochondrial protein. Removal of the putative N-terminal mitochondrial localization signal obviated association of PR-M with mitochondria, whereas addition of the mitochondrial localization signal to green fluorescent protein resulted in mitochondrial localization. Immunoelectron microscopy and Western blot analysis after mitochondrial fractionation identified PR-M in the outer mitochondrial membrane. Antibody specificity was shown by mass spectrometry identification of a PR peptide in a mitochondrial membrane protein isolation. Cell models of overexpression and gene silencing of PR-M demonstrated a progestin-induced increase in mitochondrial membrane potential and an increase in oxygen consumption consistent with an increase in cellular respiration. This is the first example of a truncated steroid receptor, lacking a DNA-binding domain that localizes to the mitochondrion and initiates direct non-nuclear progesterone action. We hypothesize that progesterone may directly affect cellular energy production to meet the increased metabolic demands of pregnancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Pairing / genetics
  • Blotting, Northern
  • Cell Line, Tumor
  • Cell Respiration / drug effects
  • Female
  • Humans
  • Mass Spectrometry
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / ultrastructure
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / ultrastructure
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism
  • Oxygen / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Progestins / pharmacology
  • Protein Transport / drug effects
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Progesterone / chemistry
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*


  • Mitochondrial Proteins
  • PR-M protein, human
  • Peptides
  • Progestins
  • RNA, Messenger
  • Receptors, Progesterone
  • Oxygen