Mitochondrial proteases act on STARD3 to activate progesterone synthesis in human syncytiotrophoblast
Por:
Esparza-Perusquía M., Olvera-Sánchez S., Flores-Herrera O., Flores-Herrera H., Guevara-Flores A., Pardo J.P., Espinosa-García M.T., Martínez F.
Publicada:
1 ene 2015
Resumen:
Background: STARD1 transports cholesterol into mitochondria of acutely regulated steroidogenic tissue. It has been suggested that STARD3 transports cholesterol in the human placenta, which does not express STARD1. STARD1 is proteolytically activated into a 30-kDa protein. However, the role of proteases in STARD3 modification in the human placenta has not been studied. Methods: Progesterone determination andWestern blot using anti-STARD3 antibodies showed that mitochondrial proteases cleave STARD3 into a 28-kDa fragment that stimulates progesterone synthesis in isolated syncytiotrophoblast mitochondria. Protease inhibitors decrease STARD3 transformation and steroidogenesis. Results: STARD3 remained tightly bound to isolated syncytiotrophoblastmitochondria. Simultaneous to the increase in progesterone synthesis, STARD3 was proteolytically processed into four proteins, of which a 28-kDa protein was themost abundant. This protein stimulatedmitochondrial progesterone production similarly to truncated-STARD3. Maximum levels of protease activity were observed at pH 7.5 and were sensitive to 1,10-phenanthroline, which inhibited steroidogenesis and STARD3 proteolytic cleavage. Addition of 22(R)-hydroxycholesterol increased progesterone synthesis, even in the presence of 1,10-phenanthroline, suggesting that proteolytic products might be involved in mitochondrial cholesterol transport. Conclusion: Metalloproteases fromhuman placental mitochondria are involved in steroidogenesis through the proteolytic activation of STARD3. 1,10-Phenanthroline inhibits STARD3 proteolytic cleavage. The 28-kDa protein and the amino terminal truncated-STARD3 stimulate steroidogenesis in a comparable rate, suggesting that both proteins share similar properties, probably the START domain that is involved in cholesterol binding. General significance: Mitochondrial proteases are involved in syncytiotrophoblast-cell steroidogenesis regulation. Understanding STARD3 activation and its role in progesterone synthesis is crucial to getting insight into its action mechanism in healthy and diseased syncytiotrophoblast cells. © 2014 Elsevier Ltd. All rights reserved.
Filiaciones:
Esparza-Perusquía M.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Olvera-Sánchez S.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Flores-Herrera O.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Flores-Herrera H.:
Departamento de Bioquímica y Biología Molecular, Instituto Nacional de Perinatología Isidro Espinosa de Los Reyes, Mexico
Guevara-Flores A.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Pardo J.P.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Espinosa-García M.T.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Martínez F.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
|