The placenta is a transitory organ that has the function of maintaining the mother-fetus relationship in order to bring the fetus to term in viable conditions. In order to achieve this objective, the placenta carries out multiple functions such as hormone synthesis and the transportation of nutrients, which help to maintain both the fetus and the placental tissue.
Among the hormones synthesized by the placenta, steroids are important because progesterone production is vital for pregnancy since any decrease or alteration in its synthesis causes a miscarriage.
Progesterone is synthesized in the mitochondria from maternal cholesterol which implies that cholesterol must cross from the maternal blood stream to the mitochondria of the placenta. Furthermore, the mitochondria also participate in the synthesis of ATP which is the source of cell energy for the placenta's transportation systems.
The study model are syncytiotrophoblast cell mitochondria which are the placenta cells active in the production of ATP and progesterone. We have shown that the isolated mitochondria of this cell group are an adequate model for the study of the placental functions, object of our research.
In our laboratory, the mechanisms related to progesterone and ATP synthesis regulation are being studied since their synthesis requires reduced coenzymes NADP+ and NAD+, respectively, which come from common substrates. The fact that the concentrations of cytochrome oxidase and cytochrome P450scc are almost the same suggests mitochondrial alternance between energy production in the form of ATP and progesterone synthesis. Therefore the existence of a mechanism that regulates the selective reduction of the coenzymes according to mitochondrial metabolism is put forward.
It has been observed that ATP synthesis, indirectly determined by oxygen consumption, is modified in the presence of different respiratory substrates and through experimentation. We have described the role of the membrane potential in the modulation of this activity and the presence of mono and divalent ions. At present, the effect of potassium and calcium on mitochondrial respiration, nucleotide hydrolysis and progesterone synthesis is being studied.
Furthermore, we have described the presence of an ATP-diphosphohydrolase which is associated with the mitochondria and would seem to participate in the phosphorylation of at least three proteins that we have not yet identified in the regulation of the cytosolic levels of adenosine and in mitochondrial cholesterol transportation.
We recently reported that cholesterol transportation is mediated by a protein system associated with binding points and probably with ATP-diphosphohydrolase. A new porine, which has not been described in any other cell type, would seem to intervene in this system since data from the preliminary sequence of this protein reveal an amino terminal that has not been found in any porine reported, while showing internal homology with several porines. We are carrying out molecular biology experiments to isolate the gene and obtain the total sequence of this new porine and to determine its role in cholesterol transportation.
In this sense, it has been reported that cholesterol transport regulation could be mediated by peripheral benzodiazepine receptors, located in the external mitochondrial membrane, possibly on facilitating the formation of binding points. The isolation of these receptors is always accompanied by a protein called VDAC (Voltage Dependent Anion Channel), a porine that could be associated with our results of the new porine.
In order to discover the possible relation of the peripheral benzodiazepine receptors, we have begun to culture trophoblast cells to determine if it is the progesterone synthesis regulation mechanism. This is also an adequate model for studying cholesterol transportation from the plasma membrane to the mitochondria, which has also been postulated as a possible mechanism in the regulation of this hormone.
Research is also being done into other point binding proteins such as thermal shock proteins which could comprise a cholesterol transportation system since the proteins related to cholesterol transportation described in other steroidogenic tissues are not found in the placenta.
WORK DONE IN COLLABORATION
BIBLIOGRAPHY
Publications from 1997 to date: