Reproductive Functions of the Mitochondrial Progesterone Receptor (PR-M).

Classic transcriptional regulation by progesterone via the nuclear progesterone receptors A and B (PR-A, PR-B) has been recognized for decades. Less attention has been given to a mitochondrial progesterone receptor (PR-M) responsible for non-nuclear activities. PR-M is derived from the progesterone receptor (PR) gene from an alternate promoter with the cDNA encoding a unique 5' membrane binding domain followed by the same hinge and hormone-binding domain of the nPR. The protein binds to the mitochondrial outer membrane and functions to increase cellular respiration via increased beta-oxidation and oxidative phosphorylation with resulting adenosine triphosphate (ATP) production. Physiologic activities of PR-M have been studied in cardiac function, spermatozoa activation, and myometrial growth, all known to respond to progesterone. Progesterone via PR-M increases cardiomyocyte cellular respiration to meet the metabolic demands of pregnancy with increased contractility. Consequential gene changes associated with PR-M activation include production of proteins for sarcomere development and for fatty acid oxidation. Regarding spermatozoa function, progesterone via PR-M increases cellular energy production necessary for progesterone-dependent hyperactivation. A role of progesterone in myometrial and leiomyomata growth may also be explained by the increase in necessary cellular energy for proliferation. Lastly, the multi-organ increase in cellular respiration may contribute to the progesterone-dependent increase in metabolic rate reflected by an increase in body temperature through compensatory non-shivering thermogenesis. An evolutionary comparison shows PR-M expressed in humans, apes, and Old World monkeys, but the necessary gene sequence is absent in New World monkeys and lower species. The evolutionary advantage to PR-M remains to be defined, but its presence may enhance catabolism to support the extended gestation and brain development found in these primates.