TY - JOUR
T1 - KH-17, a simplified derivative of bongkrekic acid, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane
AU - Takegawa, Kazuto
AU - Ito, Takeshi
AU - Yamamoto, Atsushi
AU - Yamazaki, Naoshi
AU - Shindo, Mitsuru
AU - Shinohara, Yasuo
N1 - Funding Information:
We are grateful to Fujimitsu‐Hasegawa Company for providing fresh bovine heart as the source of mitochondria. We are also deeply indebted to Dr. Keijo Fukushima and Prof. Hiromichi Fujino for their helpful advice on the statistical analysis. This study was supported by grants‐in‐aid for scientific research (No. 20K05750 [to Y.S.]) from the Ministry of Education, Science, and Culture of Japan. The study was also performed under the Research Program (No. 20221031 [to Y.S.]) “Network Joint Research Center for Materials and Devices.”
Funding Information:
We are grateful to Fujimitsu-Hasegawa Company for providing fresh bovine heart as the source of mitochondria. We are also deeply indebted to Dr. Keijo Fukushima and Prof. Hiromichi Fujino for their helpful advice on the statistical analysis. This study was supported by grants-in-aid for scientific research (No. 20K05750 [to Y.S.]) from the Ministry of Education, Science, and Culture of Japan. The study was also performed under the Research Program (No. 20221031 [to Y.S.]) “Network Joint Research Center for Materials and Devices.”
Publisher Copyright:
© 2022 John Wiley & Sons Ltd.
PY - 2023/4
Y1 - 2023/4
N2 - Two natural products, bongkrekic acid and carboxyatractyloside, are known to specifically inhibit the mitochondrial ADP/ATP carrier from its matrix side and cytosolic side, respectively, in concentration ranges of 10−6 M. In the present study, we investigated the manner of action of a synthetic bongkrekic acid derivative, KH-17, lacking three methyl groups, one methoxy group, and five internal double bonds, on the mitochondrial ADP/ATP carrier. At slightly acidic pH, KH-17 inhibited mitochondrial [3H]ADP uptake, but its inhibitory action was about 10 times weaker than that of its parental compound, bongkrekic acid. The main site of action of KH-17 was confirmed as the matrix side of the ADP/ATP carrier by experiments using submitochondrial particles, which have an inside-out orientation of the inner mitochondrial membrane. However, when we added KH-17 to mitochondria at neutral pH, it had a weak inhibitory effect on [3H]ADP uptake, and its inhibitory strength was similar to that of bongkrekic acid. These results indicated that KH-17 weakly inhibits the ADP/ATP carrier not only from the matrix side but also from the cytosolic side. To ascertain whether this interpretation was correct, we examined the effects of KH-17 and carboxyatractyloside on mitochondrial [3H]ADP uptake at two [3H]ADP concentrations. We found that both KH-17 and carboxyatractyloside showed a stronger inhibitory effect at the lower [3H]ADP concentration. Therefore, we concluded that the bongkrekic acid derivative, KH-17, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane. These results suggested that the elimination of three methyl groups, one methoxy group, and five internal double bonds present in bongkrekic acid altered its manner of action towards the mitochondrial ADP/ATP carrier. Our data will help to improve our understanding of the interaction between bongkrekic acid and the mitochondrial ADP/ATP carrier.
AB - Two natural products, bongkrekic acid and carboxyatractyloside, are known to specifically inhibit the mitochondrial ADP/ATP carrier from its matrix side and cytosolic side, respectively, in concentration ranges of 10−6 M. In the present study, we investigated the manner of action of a synthetic bongkrekic acid derivative, KH-17, lacking three methyl groups, one methoxy group, and five internal double bonds, on the mitochondrial ADP/ATP carrier. At slightly acidic pH, KH-17 inhibited mitochondrial [3H]ADP uptake, but its inhibitory action was about 10 times weaker than that of its parental compound, bongkrekic acid. The main site of action of KH-17 was confirmed as the matrix side of the ADP/ATP carrier by experiments using submitochondrial particles, which have an inside-out orientation of the inner mitochondrial membrane. However, when we added KH-17 to mitochondria at neutral pH, it had a weak inhibitory effect on [3H]ADP uptake, and its inhibitory strength was similar to that of bongkrekic acid. These results indicated that KH-17 weakly inhibits the ADP/ATP carrier not only from the matrix side but also from the cytosolic side. To ascertain whether this interpretation was correct, we examined the effects of KH-17 and carboxyatractyloside on mitochondrial [3H]ADP uptake at two [3H]ADP concentrations. We found that both KH-17 and carboxyatractyloside showed a stronger inhibitory effect at the lower [3H]ADP concentration. Therefore, we concluded that the bongkrekic acid derivative, KH-17, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane. These results suggested that the elimination of three methyl groups, one methoxy group, and five internal double bonds present in bongkrekic acid altered its manner of action towards the mitochondrial ADP/ATP carrier. Our data will help to improve our understanding of the interaction between bongkrekic acid and the mitochondrial ADP/ATP carrier.
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U2 - 10.1111/cbdd.14194
DO - 10.1111/cbdd.14194
M3 - Article
C2 - 36527173
AN - SCOPUS:85145418008
SN - 1747-0277
VL - 101
SP - 865
EP - 872
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 4
ER -