The Mitochondrial Progesterone Receptor (PR-M) In Human Sperm

Limon9

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Haidut has written threads elsewhere about the necessity of the CatSper for male fertility, a calcium channel activated by progestogens:

Male Fertility Depends On Intensity Of (sperm) Metabolism

... but did you know it expresses the "mitochondrial progesterone receptor" Dr. Peat talked about in his newsletters? This is a partial receptor lacking the DNA-binding domain, thus having essentially no genomic function. It had been overlooked in sperm due to its invisibility on Western blotting. But it's important, with its activation directly causing cell-polarization and an increase in respiratory rate.
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Expression of a mitochondrial progesterone receptor in human spermatozoa correlates with a progestin-dependent increase in mitochondrial membrane potential.
Andrology. 2014 Nov;2(6):875-83. [deep breath] Tantibhedhyangkul J, Hawkins KC, Dai Q, Mu K, Dunn CN, Miller SE, Price TM.

"A role for progesterone in sperm function has been investigated for many years with in vitro data supporting chemo-attraction (Teves, et al., 2006), capacitation, modulation of hyperactivated motility and the acrosome reaction (AR)."
"Although the majority of sperm show a progesterone-induced increase in Ca2+, less than 50% undergo an AR (Herrero, et al., 1997) for unclear reasons. The role of a progesterone receptor (PR) in this process is supported by inhibition by an antibody (C262) directed to the hormone-binding domain (HBD) of PR (Luconi et al., 1998, Sabeur, et al., 1996). More recent data suggests that progesterone acts via the CatSper Ca2+ channel to induce extracellular Ca2+ influx (Strunker, et al., 2011)."
"Presence of a PR is further supported by immunofluorescent antibody and ligand staining (Sabeur et al., 1996, Tesarik, et al., 1992), both revealing head staining. Western blot analysis with the C262 antibody and ligand blot analysis reveal proteins of 54 and 57 kDa (Luconi et al., 1998). These proteins are not seen with antibodies to the amino-terminus or DNA-binding domain (DBD) of PR. Identification of a PR in human sperm has remained elusive. An attempt at proteomic identification after immunoprecipitation with the C262 antibody and 2-D gel electrophoresis was unsuccessful (Luconi, et al., 2002). Studies to identify transcripts reveal RT-PCR products consistent with nuclear PR despite the lack of protein detection on western analysis (Luconi et al., 2002, Sachdeva, et al., 2000)."
". . . transcript analysis shows a novel sequence derived from the distal 3rd intron of the PR gene, consistent with a mitochondrial localization signal (MLS), followed by the same sequence for exons 4 through 8 of nuclear PR. Thus, the predicted protein structure consists of an amino-terminus MLS followed by the hinge and HBD of PR. RNAi studies in T47D breast cancer cells and overexpression in TET-On HeLa cells reveal a ligand-dependent control of cellular respiration. Progestin treatment shows an increase in mitochondrial membrane potential (ψm) and oxygen consumption, consistent with increased cellular respiration (Dai et al., 2013)."
"In this study, we report the expression of PR-M in human sperm and a progestin-dependent increase in ψm. These observations suggest a new mechanism whereby progesterone may increase sperm energy production to facilitate fertilization."
"Semen specimens were obtained from men who were evaluated for infertility at the Duke Fertility Center and from healthy volunteers. . . . [for testing, hopefully]"
"A total protein preparation of sperm (panel A) shows a 38 kDa protein consistent with PR-M with hybridization with a polyclonal antibody (C19) directed to the HBD of PR. A non-specific smear is noted at ~75 kDa. There is no evidence of nuclear (n) PR bands. Replacing the primary antibody with normal rabbit IgG showed no binding."
". . . both antibodies directed to the HBD (MAB 462 and C19), showed specific staining of the mid-piece, co-localizing with the mitochondrial staining, while no staining was seen with antibodies directed to the Nterminus of PR."
"Figure 4A shows an increase in ψm with a 90 min treatment with R5020 (F(3,12) = 5.4, p = . 014), with the 10-6 M dose being greater than the EtOH vehicle, p = .010; while the comparison of 10-6 M dose to the 10-8 M dose showed a p = .069. There was a significant linear trend increase in ψm among the treatments, p = 0.002."
"Nuclear PR A and B are not expressed in mature human spermatozoa leaving the option of progesterone interaction with a novel, nonnuclear PR or with proteins not homologous to the established nuclear PR. In this study, we focus on the former possibility after previous identification of a mitochondrial progesterone receptor (PR-M) (Dai et al., 2013, Saner et al., 2003), shown to increase cellular respiration."
"Treatment with the progestin R5020 increased ψm which was inhibited by a specific PR antagonist. This was not due to induction of an AR as the progestin treated sperm had no higher AR rate than did vehicle treated. This study did not determine the mechanism of the progestin-mediated increased ψm. An increase in mitochondrial membrane potential may be due to; 1) an increase in proton pumping by increased activity of respiratory enzyme complexes and consequential ATP production, 2) a transient block of electron transfer, 3) a transient block of proton use by enzymes within the mitochondria and 4) a change in the mitochondrial pH leading to a change in membrane potential (Zorov, et al., 2006). Previous indirect and direct studies in different cell types suggest the progestin-dependent increase in ψm is associated with increased cellular respiration (Behera, et al., 2009, Dai et al., 2013) (Turner, 2003)(Storey and Kayne, 1975, Travis, et al., 2001)(Miki, et al., 2004)."
"Our study did not explore an interaction of estrogen with PR-M. Binding of estradiol to a plasma membrane protein in human sperm results in inhibition of progesterone-induced Ca2+ influx and progesterone-dependent AR (Baldi, et al., 2000). Whether estradiol would also have an effect of progesterone-dependent ψm remains to be investigated."
"There is a correlation between increased mitochondrial membrane potential and motility and fertilization; whereas a decrease in mitochondrial number and proteins of the electron transport chain are found in poor quality sperm (Amaral et al., 2013)."
 

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