A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling

Abstract

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.

Expression of Mitochondrial Progesterone Receptor (PR-M) in Ovarian Cancer and Its Effect on Cell Metastasis Induced by Progesterone

“…However, such PR subtype lacks DNA binding domain and nuclear localization sequence (16). As revealed from the results, the enrichment of PR-M showed a correlation with the distribution of mitochondria, and PR-M was signi cantly expressed in heart, liver and uterine smooth muscle (23,31,32). Under the induction of progesterone, PR-M can hyperpolarize the mitochondrial membrane potential, which has been veri ed to be associated with the expression of PR-M in breast cancer cell lines mcf10a and T47D.…”

“…According to the latest research ndings, PR-M expressing state in rat H9c2 cardiomyocytes led to an elevation of oxidative cellular respiration and beta-oxidation that is determined by ligand (23). Given the mentioned analysis, PR-M expressing state in ovarian cancer tissues and non-cancer tissues was further explored, the proliferation and migration of ovarian cancer cells exhibiting high PR-M expression were observed by different concentrations of progesterone, and then the effect of progesterone on ovarian cancer from the non-genomic effect was determined.…”

Global signalling network analysis of luminal T47D breast cancer cells in response to progesterone

“…Mitochondrial PR (PR-M) is a truncated isoform of the nuclear progesterone receptors PRB and PRA, which lacks the N-terminal DNA binding domain present in PRA and PRB but does contain the hinge region responsible for dimerization and the ligand binding domain ( 55 ). PR-M has been shown to increase cellular respiration hence cell energy levels in response to ligand in various physiological situations and animal models ( 56 ). Therefore, the coordinated phosphorylation of proteins within the mitochondria in response to ligand ( Figure S4F ) may provide an interesting insight into a possible crosstalk between mitochondrial PR-M and the nuclear receptors PRA and PRB.…”

Signalling Network of Breast Cancer Cells in Response to Progesterone

“…Mitochondrial PR (PR-M) is a truncated isoform of the nuclear progesterone receptors PRB and PRA, which lacks the N-terminal DNA binding domain present in PRA and PRB but does contain the hinge region responsible for dimerization and the ligand binding domain (Price and Dai, 2015). PR-M has been shown to increase cellular respiration hence cell energy levels in response to ligand in various physiological situations and animal models (Dai et al, 2019). Therefore, the coordinated phosphorylation of proteins within the mitochondria in response to ligand (Fig.…”