Mitochondria from human term placenta. III. The role of respiration and energy generation in progesterone biosynthesis.

The interrelationships among the processes of progesterone biosynthesis, respiration and energy production in human term placental mitochondria were examined. All substrates (citrate, isocitrate, alpha-ketoglutarate, succinate, fumarate, malate, glutamate, glycerol 3-phosphate, ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine) previously found to stimulate oxygen uptake and ATP synthesis in placental mitochondria supported progesterone synthesis from endogenous and exogenous cholesterol. Citrate support of progesterone synthesis was stimulated by NADP+ but not NAD+. It was inhibited by fluorocitrate and trans-aconitate but not by arsenite, rotenone, antimycin, cyanide or 2,4-dinitrophenol. Ascorbate-N,N,N',N'-tetramethyl-p-phenylenediamine support of progesterone synthesis was stimulated by NAD+ and NADP+ and was inhibited by ADP, rotenone, antimycin, cyanide and 2,4-dinitrophenol. Cyanide inhibition was relieved by an exogenous ATP regenerating system and ADP inhibition was reversed by oligomycin. Progesterone synthesis supported by alpha-ketoglutarate + malonate was stimulated by NAD+ and NADP+, and was completely inhibited by arsenite. 2,4-Dinitrophenol was strongly inhibitory both in the absence and presence of rotenon or antimycin. Stimulation by ATP was enhanced by rotenon, antimycin and oligomycin and inhibited by 2,4-dinitrophenol. Thus, metabolic control of progesterone synthesis by the energy status of the mitochondrial system was demonstrated when reducing equivalents were supplied via NADH or the respiratory electron transport chain.