Effects of atractyligenin and its structural analogues on oxidative phosphorylation and on the translocation of adenine nucleotides in mitochondria

Abstract

1.Atractyligenin, as well as several other diterpenoid derivatives, steviol, dihydrosteviol, 7-hydroxykaurenolide, 13-hydroxystevane, diketoatractyligenin methyl ester, atractylitriol, dihydroatractylitriol, which are structural analogues of atractyligenin, exhibit an inhibitory action on oxidative phosphorylation without any uncoupling effect.2.The inhibition of respiration and coupled phosphorylation caused by atractyligenin is competitively reversed by ADP. The Ki of atractyligenin is 1.5·10−5 M.3.The inhibition of mitochondrial respiration due to atractyligenin only involves the stimulation of respiration resulting from addition of exogenous ADP to mitochondria.4.The 2,4-dinitrophenol-stimulated respiration is insensitive to atractyligenin.5.Atractyligenin inhibits the 2,4-dinitrophenol-stimulated ATPase activity.6.Atractyligenin competitively inhibits the translocation of adenine nucleotides in mitochondria.7.Steviol and dihydrosteviol behave similarly to atractyligenin in many respects. In particular, they inhibit the mitochondrial translocation of adenine nucleotides. However, ADP does not antagonize competitively the effects of steviol and dihydrosteviol.8.The following compounds do not affect the translocation of adenine nucleotides but they inhibit electron transfer between NADH and cytochrome b in the respiratory chain: 7-hydroxykaurenolide, 13-hydroxystevane, atractylitriol, dihy-droatractylitriol and diketoatractyligenin methyl ester.9.The effect of atractyligenin, steviol and dihydrosteviol is interpreted on the basis of an analogy between these derivatives and a mitochondrial compound, possibly a steroid, behaving as an allosteric activator in the translocation of adenine nucleotides. Atractyligenin, as well as several other diterpenoid derivatives, steviol, dihydrosteviol, 7-hydroxykaurenolide, 13-hydroxystevane, diketoatractyligenin methyl ester, atractylitriol, dihydroatractylitriol, which are structural analogues of atractyligenin, exhibit an inhibitory action on oxidative phosphorylation without any uncoupling effect. The inhibition of respiration and coupled phosphorylation caused by atractyligenin is competitively reversed by ADP. The Ki of atractyligenin is 1.5·10−5 M. The inhibition of mitochondrial respiration due to atractyligenin only involves the stimulation of respiration resulting from addition of exogenous ADP to mitochondria. The 2,4-dinitrophenol-stimulated respiration is insensitive to atractyligenin. Atractyligenin inhibits the 2,4-dinitrophenol-stimulated ATPase activity. Atractyligenin competitively inhibits the translocation of adenine nucleotides in mitochondria. Steviol and dihydrosteviol behave similarly to atractyligenin in many respects. In particular, they inhibit the mitochondrial translocation of adenine nucleotides. However, ADP does not antagonize competitively the effects of steviol and dihydrosteviol. The following compounds do not affect the translocation of adenine nucleotides but they inhibit electron transfer between NADH and cytochrome b in the respiratory chain: 7-hydroxykaurenolide, 13-hydroxystevane, atractylitriol, dihy-droatractylitriol and diketoatractyligenin methyl ester. The effect of atractyligenin, steviol and dihydrosteviol is interpreted on the basis of an analogy between these derivatives and a mitochondrial compound, possibly a steroid, behaving as an allosteric activator in the translocation of adenine nucleotides.